A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts

Abstract

Background: Cyclic high-dose testosterone injections, also known as bipolar androgen therapy (BAT), is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). BAT has shown clinical activity in prior studies enrolling men with mCRPC and may potentially restore sensitivity to prior androgen receptor (AR)-targeted agents.

Objective: To evaluate the clinical activity of BAT in patients progressing on AR-targeted therapy as well as responses to abiraterone or enzalutamide upon rechallenge after BAT.

Design, setting, and participants: RESTORE is a multicohort phase II study enrolling asymptomatic mCRPC patients after abiraterone or enzalutamide at Johns Hopkins Hospital (NCT02090114). Participants (29 after abiraterone and 30 after enzalutamide) received 400 mg testosterone cypionate intramuscularly every 28 days, with ongoing luteinizing hormone-releasing hormone agonist/antagonist treatment (ie, BAT). Following progression on BAT, patients were rechallenged with their most recent AR-targeted therapy.

Outcome measurements and statistical analysis: Coprimary endpoints were >50% decline in PSA from baseline (PSA50) responses to BAT and following AR-targeted therapy rechallenge. Outcomes in the post-abiraterone cohort are presented, as well as updated results from the post-enzalutamide cohort and an exploratory AR-V7 analysis.

Results and limitations: No statistically significant difference in PSA50 response rates to BAT was observed (30% [post-enzalutamide cohort] vs 17% [post-abiraterone cohort], p = 0.4). However, PSA50 responses to AR-targeted therapy rechallenge were higher in the post-enzalutamide cohort (68% vs 16%, p = 0.001). The median time from enrollment to progression following rechallenge with AR-targeted therapy (ie, progression-free survival 2; PFS2) was longer in the post-enzalutamide versus post-abiraterone patients (12.8 vs 8.1 mo, p = 0.04). Outcomes were worse in patients with detectable AR-V7 in circulating tumor cells (median PFS2: 10.3 vs 7.1 mo, p = 0.005).

Conclusions: BAT shows clinical activity in mCRPC patients and may be more effective at resensitizing to enzalutamide versus abiraterone.

Patient summary: BAT is well tolerated in metastatic castration-resistant prostate cancer patients. The type of prior AR-targeted therapy might affect response to BAT as well as AR-therapy rechallenge. BAT followed by AR-targeted therapy rechallenge did not improve outcomes in AR-V7-positive patients.

Keywords: Androgen receptor–targeted therapy; Bipolar androgen therapy; Testosterone.

Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1 –

Clinical benefit of BAT and abiraterone rechallenge in the post-abiraterone cohort. (A) Waterfall plot of best PSA response to BAT and (B) abiraterone rechallenge following BAT. A >50% decline in PSA from baseline (PSA50) from baseline is shown via the dotted line. (C) Best percentage change in target lesion sum to BAT is shown for patients with measureable disease. Two patients achieved an objective response as denoted by a dotted line. (D) Radiographic progression-free survival (rPFS) on BAT is shown as a Kaplan-Meier curve (solid line) bracketed by a dotted line (95% confidence interval [CI]): median rPFS: 5.0 mo (95% CI: 3.3–9.3 mo). Kaplan-Meier curves demonstrated clinical or radiographic progression-free survival (crPFS) for (E) BAT (median crPFS: 4.3 mo [95% CI: 3.3–5.3 mo]) and (F) abiraterone rechallenge following BAT (median crPFS: 4.0 mo [95% CI: 3.0–4.0 mo]). BAT = bipolar androgen therapy; ORR = objective response rate; PFS = progression-free survival; PSA = prostate-specific antigen. * Values truncated at 100% (see Supplementary Table 1 for additional details).

Fig. 2 –

BAT and AR-targeted therapy rechallenge: post hoc comparison of post-enzalutamide and post-abiraterone cohorts. (A) Best PSA response to BAT (blue) and abiraterone rechallenge following BAT (red), paired for each patient in the post-abiraterone cohort. One patient was not evaluable for PSA response and is not included. (B) Best PSA response to BAT (blue) and enzalutamide rechallenge following BAT (orange), paired for each patient in the post-enzalutamide cohort. One patient was not evaluable for PSA response and is not included. PSA50 response cutoff was denoted by the dashed line. Clinical or radiographic PFS (crPFS) on (C) BAT and (D) AR-targeted therapy rechallenge, estimated with Kaplan-Meier curves, in the post-abiraterone (red) and post-enzalutamide (blue) cohorts. (E) Kaplan-Meier estimates of PFS2 in the post-abiraterone (red) and post-enzalutamide (blue) patients. AR = androgen receptor; BAT = bipolar androgen therapy; CI = confidence interval; PFS = progression-free survival; PSA = prostate-specific antigen; PSA50 = >50% decline in PSA from baseline. * Values truncated at 100% (see Supplementary Table 1 for additional details).

Fig. 3 –

Effect of AR-V7 status on clinical outcomes of BAT and AR-targeted therapy rechallenge. Clinical or radiographic PFS (crPFS) on (A) BAT and (B) AR-targeted therapy rechallenge (combined abiraterone and enzalutamide patients), estimated with Kaplan-Meier curves, in AR-V7–negative (red) and AR-V7–positive (blue) subgroups. (C) Kaplan-Meier estimates of PFS2 in AR-V7–negative (red) and AR-V7–positive (blue) subgroups. AR = androgen receptor; BAT = bipolar androgen therapy; CI = confidence interval; PFS = progression-free survival.