Extreme bipolar androgen therapy: Alternating darolutamide and testosterone cypionate in patients with metastatic castration-resistant prostate cancer (mCRPC; ExBAT trial/LACOG 0620).

Abstract

178 Background: Sequencing androgen-receptor signaling inhibitors (ARSi) has limited activity in metastatic castration-resistant prostate cancer (mCRPC). Bipolar Androgen Therapy (BAT), consisting of supraphysiological doses of exogenous testosterone, followed by a decline to castrate levels, has shown benefit in a subset of patients (pts) with mCRPC, by the downregulation of AR levels, a therapeutic vulnerability which led to resensitization to ARSi in trials. We hypothesize that BAT could significantly enhance the efficacy of subsequent ARSi darolutamide in pts who had progressed to abiraterone. Methods: The ExBAT/LACOG 0620 ( NCT04558866 ) study is a phase II, single-arm, multi-center trial investigating a pre-planned regimen of alternating BAT and darolutamide in mCRPC pts after progression on abiraterone. Prior docetaxel for hormone-sensitive disease was allowed. Pts received intramuscular testosterone cypionate 400 mg on day 1, followed by oral darolutamide 1200 mg/day from day 29 to day 56, followed by a washout period of 7 days, in 63-day cycles. The primary endpoint was radiographic progression-free survival (rPFS) at 12 months. Secondary endpoints include median rPFS, PSA50 response, overall survival (OS), quality of life (QoL) and safety. Results: From Jun2021 to Mar2023, 51 pts were enrolled in 9 centers and 48 pts were eligible for efficacy analysis. Median age was 69y (range, 48-92), 23.5% had received abiraterone on castration-sensitive setting and 76.5% on mCRPC. The rPFS rate at 12 months was 40.9% (95% CI, 26.3 – 55.0) and median rPFS was 9.0 months (95% CI, 3.9 – 12.9). PSA50 response was 16.7% (95% CI, 7.4–30.2) and median OS was 23.0 months (95% CI, 17.7 – not reached). At cut-off date (22Mar24), 10 pts remained on treatment. QoL was maintained during the treatment. Treatment-related adverse events (TRAEs) rates of any grade and grade 3-4 were 64.7% and 9.8% respectively, and no grade 5 TRAE was reported. The most common AEs were bone and breast pain. Conclusions: ExBAT study demonstrated durable (12 months or more) antintumor activity of alternating BAT and darolutamide in around 40% of pts, with manageble safety profile. Further studies evaluating ExBAT are needed to identify biomarkers of response and the impact of ARSi sequencing in subsequent lines of therapy. Clinical trial information: NCT04558866 .