Trial Outcomes & Findings for RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistance (The RESTORE Study) (NCT NCT02090114)

NCT ID: NCT02090114

Last Updated: 2022-06-27

Results Overview

Number of participants with ≥50% PSA reduction from pre-BAT baseline level

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 112 participants
• Primary outcome timeframe: up to 18 months
• Results posted on: 2022-06-27

Participant Flow

16 patients failed screen.

Participant milestones

Measure	Cohort A:Post-enzalutamide Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Study STARTED	30	29	29	8
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	30	29	29	8

Reasons for withdrawal

Measure	Cohort A:Post-enzalutamide Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Study Withdrawal by Subject	3	6	2	1
Overall Study Physician Decision	5	0	1	1
Overall Study Adverse Event	1	2	2	0
Overall Study Progressive Disease	20	21	23	6
Overall Study Death	1	0	1	0

Baseline Characteristics

RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistance (The RESTORE Study)

Baseline characteristics by cohort

Measure	Cohort A:Post-enzalutamide n=30 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=29 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 Participants Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation n=8 Participants Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Total n=96 Participants Total of all reporting groups
Age, Continuous	74 Years n=5 Participants	71 Years n=7 Participants	69 Years n=5 Participants	73 Years n=4 Participants	72 Years n=21 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Sex: Female, Male Male	30 Participants n=5 Participants	29 Participants n=7 Participants	29 Participants n=5 Participants	8 Participants n=4 Participants	96 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	24 Participants n=5 Participants	26 Participants n=7 Participants	24 Participants n=5 Participants	7 Participants n=4 Participants	81 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	6 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	0 Participants n=4 Participants	13 Participants n=21 Participants
Race/Ethnicity, Customized White	27 Participants n=5 Participants	26 Participants n=7 Participants	23 Participants n=5 Participants	7 Participants n=4 Participants	83 Participants n=21 Participants
Race/Ethnicity, Customized Non-white	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants	1 Participants n=4 Participants	13 Participants n=21 Participants
Region of Enrollment United States	30 Participants n=5 Participants	29 Participants n=7 Participants	29 Participants n=5 Participants	8 Participants n=4 Participants	96 Participants n=21 Participants

PRIMARY outcome

Timeframe: up to 18 months

Population: Only 7/8 patients were evaluable from Cohort D.

Number of participants with ≥50% PSA reduction from pre-BAT baseline level

Outcome measures

Measure	Cohort A:Post-enzalutamide n=30 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=29 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 Participants Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation n=7 Participants Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Prostate Specific Antigen (PSA) Response to Bipolar Androgen Therapy (BAT)	9 Participants	5 Participants	4 Participants	2 Participants

PRIMARY outcome

Timeframe: up to 24 months

Population: This outcome measure only applies to cohort A,B, and D. Only 22/30 (Cohort A), 19/29 (Cohort B) and 7/8 (Cohort D) patients had evaluable data.

Number of participants with ≥50% PSA reduction after enzalutamide or abiraterone acetate post-BAT from baseline

Outcome measures

Measure	Cohort A:Post-enzalutamide n=22 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=19 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation n=7 Participants Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
PSA Response to Enzalutamide or Abiraterone Acetate Post Bipolar Androgen Therapy	15 Participants	3 Participants	—	2 Participants

SECONDARY outcome

Timeframe: up to 18 months

Population: Only 21/30 participants were evaluable from Cohort A. Only 19/29 participants were evaluable from Cohort B.This outcome measure does not apply to Cohort D.

Time to PSA progression on enzalutamide or abiraterone acetate or return to castrate levels of testosterone post-BAT, defined as the time from the date of re-initiation of enzalutamide or abiraterone acetate or castration-only therapy to the date of the PSA measurement when it shows an increase by ≥25% above the nadir value that occurred following re-initiation of enzalutamide or abiraterone acetate or castration-only therapy and confirmed by a repeat PSA 4 weeks later (PCWG2).

Outcome measures

Measure	Cohort A:Post-enzalutamide n=21 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=19 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 Participants Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
PSA Progression on Enzalutamide or Abiraterone Acetate or Castrate Levels Post-BAT	5.5 months Interval 4.6 to insufficient number of participants with events	3.7 months Interval 1.5 to 5.0	NA months insufficient number of participants with events	—

SECONDARY outcome

Timeframe: up to 18 months

Time to PSA progression on BAT. Time to PSA progression on BAT is defined as the time from the date of initial dose of Testosterone to the date of the PSA measurement when it shows an ≥25% increase above the nadir value and confirmed by a repeat PSA 4 weeks later (PCWG2 criteria) during the treatment with BAT.

Outcome measures

Measure	Cohort A:Post-enzalutamide n=30 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=29 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 Participants Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation n=7 Participants Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
PSA Progression on BAT (Bipolar Androgen Therapy )	3.3 months Interval 2.7 to 5.5	3.2 months Interval 2.5 to 6.0	0.93 months Interval 0.93 to 5.58	3 months Interval 2.8 to insufficient number of participants with events

SECONDARY outcome

Timeframe: up to 18 months

Population: 12/30 participants from Cohort A, 7/29 participants from Cohort B, 13/20 from Cohort C, and 7/8 participants from Cohort D were evaluable for this outcome measure.

Number of participants with complete or partial response post-BAT as defined by RECIST 1.1 (for soft tissue lesions) and PCWG2 criteria (for bone disease), or return to castration-only post-BAT.

Outcome measures

Measure	Cohort A:Post-enzalutamide n=12 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=7 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=13 Participants Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation n=7 Participants Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Disease Response as Defined by RECIST 1.1 (Soft Tissue Lesions) and PCWG2 Criteria (Bone Lesions)	6 Participants	2 Participants	4 Participants	0 Participants

SECONDARY outcome

Timeframe: up to 18 months

Population: Data was not collected to assess this outcome measure.

Time to initiation of docetaxel chemotherapy

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: up to 18 months

Population: 25/30 participants in Cohort A, 22/29 participants in Cohort B, 28/29 participants in Cohort C were evaluable for this outcome measure. Data was not collected from participants for Cohort D.

Functional Assessment of Chronic Illness Therapy, Fatigue Subscale (FACIT-F) assesses Fatigue with a total score range of 0-52, with a higher score reflecting better QoL.

Outcome measures

Measure	Cohort A:Post-enzalutamide n=25 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=29 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 Participants Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Quality of Life (QoL) as Assessed by FACIT-F Score Baseline	13.28 score on a scale Standard Deviation 6.73	16.86 score on a scale Standard Deviation 7.62	13 score on a scale Standard Deviation 5.57	—
Quality of Life (QoL) as Assessed by FACIT-F Score Cycle 1 Day 85	10.64 score on a scale Standard Deviation 5.51	13.85 score on a scale Standard Deviation 7.42	11.55 score on a scale Standard Deviation 3.39	—

SECONDARY outcome

Timeframe: 18 months

Population: In cohort D, data was only collected from 7/8 participants.

Number of participants who experience adverse events, as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

Outcome measures

Measure	Cohort A:Post-enzalutamide n=30 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=29 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 Participants Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation n=7 Participants Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Safety and Tolerability as Assessed by Number of Participants With Adverse Events	30 Participants	29 Participants	29 Participants	7 Participants

SECONDARY outcome

Timeframe: up to 18 months

Population: 25/30 participants in Cohort A, 19/29 participants in Cohort B, 25/29 participants in Cohort C were evaluable for this outcome measure. Data was not collected from participants in Cohort D.

RAND 36-Item Short Form (RANDSF-36) assesses physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, general health perceptions, and perceived change in health with a total score range of 0-100. The total score from all of the questions answered is divided by the total number of the questions answered yielding a global score from 0-100, with a higher score reflecting a better QoL.

Outcome measures

Measure	Cohort A:Post-enzalutamide n=30 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=29 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 Participants Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Quality of Life (QoL) as Assessed by RANDSF-36 Baseline	72.23 score on a scale Standard Deviation 18.89	64.36 score on a scale Standard Deviation 18.70	69.72 score on a scale Standard Deviation 17.72	—
Quality of Life (QoL) as Assessed by RANDSF-36 Cycle 1 Day 85	71.76 score on a scale Standard Deviation 19.20	73.97 score on a scale Standard Deviation 19.96	73.40 score on a scale Standard Deviation 17.98	—

SECONDARY outcome

Timeframe: up to 18 months

Population: Data was not collected for this outcome measure.

Brief Pain Inventory (BPI) assesses the severity of pain and its impact on functioning with scales ranging from 0-10, with a higher score indicating a higher level of pain.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: up to 18 months

Population: 20/30 participants in Cohort A, 21/29 participants in Cohort B, 25/29 participants in Cohort C were evaluable for this outcome measure. Data was not collected from participants in Cohort D.

International Index of Erectile Function (IIEF-5) is a diagnostic tool for erectile dysfunction, with a total score range of 5-25, with the lowest score indicating a higher degree of dysfunction.

Outcome measures

Measure	Cohort A:Post-enzalutamide n=30 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=29 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 Participants Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Quality of Life (QoL) as Assessed by IIEF Baseline	8 score on a scale Standard Deviation 3.57	7.33 score on a scale Standard Deviation 3.89	12.56 score on a scale Standard Deviation 12.86	—
Quality of Life (QoL) as Assessed by IIEF BAT C1D85	24.13 score on a scale Standard Deviation 21.63	24.94 score on a scale Standard Deviation 19.71	22.44 score on a scale Standard Deviation 15.53	—

SECONDARY outcome

Timeframe: up to 18 months

Population: 20/30 participants in Cohort A, 18/29 participants in Cohort B, 25/29 participants in Cohort C were evaluable for this outcome measure. Data was not collected for Cohort D.

Positive and Negative Affect Schedule (PANAS) is a self-report measure that is made up of two mood scales, one measuring positive affect and the other measuring negative affect, with a total score range from 10-50 with a higher score on the positive scale indicating greater levels of positive affect and a lower score on the negative scale indicating less of a negative affect.

Outcome measures

Measure	Cohort A:Post-enzalutamide n=30 Participants Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=29 Participants Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 Participants Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Quality of Life (QoL) as Assessed by PANAS Baseline	46.15 score on a scale Standard Deviation 10.55	48 score on a scale Standard Deviation 11.47	41.24 score on a scale Standard Deviation 14.35	—
Quality of Life (QoL) as Assessed by PANAS BAT C1D85	45.1 score on a scale Standard Deviation 9.09	45.22 score on a scale Standard Deviation 12.94	44.48 score on a scale Standard Deviation 11.06	—

Adverse Events

Cohort A:Post-enzalutamide

Serious events: 3 serious events

Other events: 30 other events

Deaths: 1 deaths

Cohort B: Post-abiraterone

Serious events: 4 serious events

Other events: 29 other events

Deaths: 0 deaths

Cohort C: Castration Only

Serious events: 5 serious events

Other events: 29 other events

Deaths: 1 deaths

Cohort D: Mutation

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Measure	Cohort A:Post-enzalutamide n=30 participants at risk Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=29 participants at risk Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 participants at risk Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation n=8 participants at risk Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Renal and urinary disorders Urine Retention	0.00% 0/30 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Metabolism and nutrition disorders Pancreatitis, elevated lipase, amylase	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Blood and lymphatic system disorders disseminated intravascular coagulation	0.00% 0/30 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Nervous system disorders Neurological Symptoms	0.00% 0/30 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Respiratory, thoracic and mediastinal disorders Pneumonia	0.00% 0/30 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Renal and urinary disorders Acute Renal Insufficiency	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Cardiac disorders myocardial infarction	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Nervous system disorders stroke	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Respiratory, thoracic and mediastinal disorders dyspnea	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Cardiac disorders Cardiac Arrest	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Gastrointestinal disorders Lower gastrointestinal hemorrhage	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Infections and infestations Urinary Tract Infection	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	12.5% 1/8 • Number of events 1 • Up to 2 years

Other adverse events

Measure	Cohort A:Post-enzalutamide n=30 participants at risk Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Cohort B: Post-abiraterone n=29 participants at risk Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Cohort C: Castration Only n=29 participants at risk Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Cohort D: Mutation n=8 participants at risk Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	40.0% 12/30 • Number of events 39 • Up to 2 years	27.6% 8/29 • Number of events 23 • Up to 2 years	37.9% 11/29 • Number of events 22 • Up to 2 years	50.0% 4/8 • Number of events 7 • Up to 2 years
Blood and lymphatic system disorders Increased Hemoglobin	36.7% 11/30 • Number of events 11 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Vascular disorders Hypertension	23.3% 7/30 • Number of events 24 • Up to 2 years	13.8% 4/29 • Number of events 8 • Up to 2 years	20.7% 6/29 • Number of events 6 • Up to 2 years	0.00% 0/8 • Up to 2 years
Blood and lymphatic system disorders Anemia	16.7% 5/30 • Number of events 16 • Up to 2 years	24.1% 7/29 • Number of events 10 • Up to 2 years	0.00% 0/29 • Up to 2 years	25.0% 2/8 • Number of events 2 • Up to 2 years
Reproductive system and breast disorders Breast Tenderness	16.7% 5/30 • Number of events 5 • Up to 2 years	17.2% 5/29 • Number of events 6 • Up to 2 years	20.7% 6/29 • Number of events 6 • Up to 2 years	0.00% 0/8 • Up to 2 years
Skin and subcutaneous tissue disorders rash	16.7% 5/30 • Number of events 6 • Up to 2 years	6.9% 2/29 • Number of events 2 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
General disorders fatigue	56.7% 17/30 • Number of events 23 • Up to 2 years	17.2% 5/29 • Number of events 5 • Up to 2 years	17.2% 5/29 • Number of events 5 • Up to 2 years	0.00% 0/8 • Up to 2 years
Gastrointestinal disorders nausea	23.3% 7/30 • Number of events 9 • Up to 2 years	13.8% 4/29 • Number of events 4 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	12.5% 1/8 • Number of events 1 • Up to 2 years
Reproductive system and breast disorders gynecomastia	13.3% 4/30 • Number of events 4 • Up to 2 years	0.00% 0/29 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	12.5% 1/8 • Number of events 1 • Up to 2 years
Vascular disorders hot flashes	16.7% 5/30 • Number of events 6 • Up to 2 years	13.8% 4/29 • Number of events 4 • Up to 2 years	6.9% 2/29 • Number of events 4 • Up to 2 years	12.5% 1/8 • Number of events 1 • Up to 2 years
Skin and subcutaneous tissue disorders pruritis	13.3% 4/30 • Number of events 4 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Gastrointestinal disorders abdominal pain	10.0% 3/30 • Number of events 3 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	10.3% 3/29 • Number of events 3 • Up to 2 years	0.00% 0/8 • Up to 2 years
General disorders edema	13.3% 4/30 • Number of events 5 • Up to 2 years	27.6% 8/29 • Number of events 12 • Up to 2 years	24.1% 7/29 • Number of events 8 • Up to 2 years	12.5% 1/8 • Number of events 3 • Up to 2 years
Injury, poisoning and procedural complications fall	10.0% 3/30 • Number of events 3 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Infections and infestations sinusitis	10.0% 3/30 • Number of events 4 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Hepatobiliary disorders gallstone	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Metabolism and nutrition disorders anorexia	10.0% 3/30 • Number of events 3 • Up to 2 years	17.2% 5/29 • Number of events 7 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	12.5% 1/8 • Number of events 1 • Up to 2 years
Nervous system disorders headache	10.0% 3/30 • Number of events 3 • Up to 2 years	17.2% 5/29 • Number of events 5 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Investigations elevated ALK Phos	0.00% 0/30 • Up to 2 years	10.3% 3/29 • Number of events 3 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Psychiatric disorders insomnia	3.3% 1/30 • Number of events 1 • Up to 2 years	6.9% 2/29 • Number of events 2 • Up to 2 years	10.3% 3/29 • Number of events 3 • Up to 2 years	0.00% 0/8 • Up to 2 years
Skin and subcutaneous tissue disorders pain at injection site	0.00% 0/30 • Up to 2 years	6.9% 2/29 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Reproductive system and breast disorders urine obstruction	0.00% 0/30 • Up to 2 years	6.9% 2/29 • Number of events 2 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Gastrointestinal disorders bowel obstruction	0.00% 0/30 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Skin and subcutaneous tissue disorders increased hair growth	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	10.3% 3/29 • Number of events 3 • Up to 2 years	0.00% 0/8 • Up to 2 years
Respiratory, thoracic and mediastinal disorders dyspnea	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	6.9% 2/29 • Number of events 2 • Up to 2 years	0.00% 0/8 • Up to 2 years
Psychiatric disorders irritability	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	6.9% 2/29 • Number of events 2 • Up to 2 years	0.00% 0/8 • Up to 2 years
Blood and lymphatic system disorders polycythemia	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Renal and urinary disorders Hematuria	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	25.0% 2/8 • Number of events 2 • Up to 2 years
General disorders fever	3.3% 1/30 • Number of events 1 • Up to 2 years	6.9% 2/29 • Number of events 2 • Up to 2 years	0.00% 0/29 • Up to 2 years	12.5% 1/8 • Number of events 1 • Up to 2 years
Gastrointestinal disorders diarrhea	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	10.3% 3/29 • Number of events 3 • Up to 2 years	12.5% 1/8 • Number of events 1 • Up to 2 years
Gastrointestinal disorders constipation	10.0% 3/30 • Number of events 3 • Up to 2 years	10.3% 3/29 • Number of events 4 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	12.5% 1/8 • Number of events 2 • Up to 2 years
Gastrointestinal disorders bloating	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	12.5% 1/8 • Number of events 1 • Up to 2 years
Nervous system disorders Syncope	6.7% 2/30 • Number of events 2 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	12.5% 1/8 • Number of events 1 • Up to 2 years
Renal and urinary disorders Urinary tract infection	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	3.4% 1/29 • Number of events 2 • Up to 2 years	25.0% 2/8 • Number of events 3 • Up to 2 years
Nervous system disorders dizziness	13.3% 4/30 • Number of events 4 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	25.0% 2/8 • Number of events 2 • Up to 2 years
Investigations weight loss	13.3% 4/30 • Number of events 4 • Up to 2 years	10.3% 3/29 • Number of events 3 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Psychiatric disorders anxiety	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Respiratory, thoracic and mediastinal disorders cough	16.7% 5/30 • Number of events 6 • Up to 2 years	13.8% 4/29 • Number of events 6 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Reproductive system and breast disorders Erectile dysfunction	0.00% 0/30 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
General disorders chest pain	6.7% 2/30 • Number of events 2 • Up to 2 years	6.9% 2/29 • Number of events 2 • Up to 2 years	6.9% 2/29 • Number of events 2 • Up to 2 years	0.00% 0/8 • Up to 2 years
Nervous system disorders Taster change	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Investigations Creatinine Increased	10.0% 3/30 • Number of events 4 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	3.4% 1/29 • Number of events 2 • Up to 2 years	12.5% 1/8 • Number of events 1 • Up to 2 years
General disorders cold symptoms	6.7% 2/30 • Number of events 2 • Up to 2 years	0.00% 0/29 • Up to 2 years	6.9% 2/29 • Number of events 2 • Up to 2 years	0.00% 0/8 • Up to 2 years
Investigations High cholesterol	10.0% 3/30 • Number of events 3 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Metabolism and nutrition disorders Elevated potassium	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Blood and lymphatic system disorders Elevated hematocrit	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Metabolism and nutrition disorders Elevated Glucose	0.00% 0/30 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Investigations Elevated liver enzymes	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Investigations Elevated AST	0.00% 0/30 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Investigations Elevated troponin	0.00% 0/30 • Up to 2 years	0.00% 0/29 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/8 • Up to 2 years
Eye disorders eye discorder	10.0% 3/30 • Number of events 3 • Up to 2 years	3.4% 1/29 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years
Respiratory, thoracic and mediastinal disorders Shortness of breath	3.3% 1/30 • Number of events 1 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/29 • Up to 2 years	0.00% 0/8 • Up to 2 years

Additional Information

Samuel Denmeade, M.D.

Johns Hopkins University School of Medicine

Phone: 410-502-8341

Email: denmesa@jhmi.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place