Bipolar Androgen Therapy (BAT) for Nonmetastatic Castration-Resistant Prostate (nmcrpc) Cancer Progressing on Darolutamide: Working out M0 BAT (WOMBAT; ANZUP 2201).

TPS298 Background: The backbone of prostate cancer systemic treatment is androgen deprivation therapy (ADT) increasingly with the use of androgen receptor pathway inhibitors (ARPIs). Mechanisms for ARPI resistance include amplification of the androgen receptor (AR), overexpression of AR variants, aberrant AR activity, and autocrine/paracrine androgen synthesis in tumour cells. Preclinical and clinical studies have identified that bipolar androgen therapy (BAT) may restore the sensitivity of prostate cancer to ARPIs. We plan to test this hypothesis in patients with PSA progression on darolutamide for non-metastatic castrate resistant prostate cancer. Methods: WOMBAT (ANZUP 2201, NCT06594926, ACTRN12624000582550) is a single-arm phase 2 trial. The primary endpoint is to determine metastasis-free survival (MFS; time from commencing BAT to evidence of metastases or death, by conventional imaging as per PCWG3 criteria). Secondary endpoints include toxicity of BAT and darolutamide; effects on health-related quality of life; efficacy measures (PSA response rate; PSA progression-free survival); effects of BAT and darolutamide on bone turnover. Inclusion criteria include: PSA progression on darolutamide for nmCRPC; M0 on conventional imaging. Treatment consists of BAT (IM testosterone enanthate 500mg) day 1 and darolutamide 600mg bd days 29-56 (of a 56-day cycle) with ongoing ADT. The total sample size of 69 (with a first stage of enrolment of 44) is calculated to demonstrate an increase in the proportion of participants without detectable metastases at 6 months from 56.1% to 66.7% (corresponding to a median MFS improvement from 7.2 to 10.27 months, HR 0.6) with a one-sided type I error of α = 10% and power of 80%, based on benchmarks from the ARAMIS trial of darolutamide in nmCRPC. Enrolment has commenced at 8 sites around Australia. Clinical trial information: ACTRN12624000582550 .