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

Abstract

TPS276 Background: Prostate cancer has an intrinsic dependence on androgens and androgen receptor (AR) regulation. Suppression of gonadal androgen synthesis known as androgen deprivation therapy (ADT), either by orchiectomy or by pharmacological modulation, represents the treatment backbone of metastatic disease. Unfortunately, almost invariably, patients develop resistance to ADT, progressing to a state called castration-resistant prostate cancer (CRPC), defined as disease progression at serum testosterone levels in the castrate range. Bipolar Androgen Therapy (BAT), consisting of exogenous supraphysiological doses of testosterone followed by castrate levels, has shown clinical activity in multiple early phase clinical trials, in addition to improvement of quality of life (QoL) in CRPC patients. Alternated administration of BAT and novel AR-targeted therapies, a strategy entitled by our group as Extreme Bipolar Androgen Therapy (ExBAT), has never been tested in patients with CRPC. The objective of our study is to assess the ExBAT approach in metastatic CRPC. Methods: ExBAT (NCT04558866) is a phase 2, single-arm, multicenter trial assessing patients with mCRPC who progressed to abiraterone by PCWG3 criteria. Prior docetaxel for metastatic hormone-sensitive disease is allowed if ≥ 12 months elapsed from last dose of docetaxel. Included patients receive testosterone cypionate 400 mg IM on day 1 followed by darolutamide 1,200 mg/day orally for 4 weeks (starting on day 29 through day 56) on 63-day cycles. The primary endpoint is radiographic progression-free survival (rPFS) at 12 months. Secondary endpoints include PSA decline rates, overall survival, toxicity, quality of life, and predictive biomarkers of response/survival. Tumor assessments are performed every 9 weeks, for the first 2 cycles and every 18 weeks thereafter up to 12 months. Patients with disease progression with clinical benefit are allowed to continue treatment. Patients without disease progression after 12 months are allowed to receive study treatment on Extension Phase. The sample size of 47 patients (considering 5% drop-out) was calculated based on the primary endpoint using a two-sided 5% significance level Chi-square Test for One Proportion and achieves 80% power to detect the difference between a 50% rPFS at 12 months comparing with 30% in the historic control group. NCT04558866. From June2021 to September2022, 31 of planned 47 patients have been enrolled in 8 Brazilian centers. Results are not available at the time of submission. Clinical trial information: NCT04558866 .