WOMBAT (ANZUP 2201): A Phase 2, Single-arm Study of Bipolar Androgen Therapy in Patients with Nonmetastatic Castration-resistant Prostate Cancer with Prostate-specific Antigen Progression on Darolutamide

BACKGROUND AND OBJECTIVE: Resistance to androgen receptor pathway inhibitors (ARPIs) such as darolutamide signals impending metastatic progression of prostate cancer (PC) with limited subsequent therapeutic options. It has been shown that bipolar androgen therapy (BAT) resensitizes castration-resistant PC (CRPC) cells to ARPIs. The objective of the WOMBAT trial is to evaluate the efficacy and safety of BAT in men with nonmetastatic CRPC (nmCRPC) experiencing biochemical-only progression on darolutamide. CLINICAL TRIAL DESIGN AND TIMEFRAME: WOMBAT is a prospective, single-arm, multicenter, phase 2 trial enrolling ∼69 participants. The trial uses a Simon optimal two-stage design with an interim futility analysis, which provides 80% power for detection of a clinically significant improvement in metastasis-free survival (MFS; hazard ratio ∼0.68). Patients receive 56-d treatment cycles comprising sequential intramuscular testosterone and intermittent oral darolutamide on a continuous androgen deprivation therapy backbone. Treatment continues until progression, with a 24-mo follow-up period. ENDPOINTS: The primary endpoint is MFS. Secondary endpoints include safety and tolerability, the prostate-specific antigen (PSA) response rate, time to PSA progression, health-related quality of life (HRQoL), and changes in metabolic and bone turnover markers. STRENGTHS AND LIMITATIONS: This is the first trial to investigate BAT in the specific clinical setting of nmCRPC progression on darolutamide. Strengths include a strong biological rationale and extensive collection of translational and HRQoL data. The single-arm design is a limitation. Furthermore, while MFS is a regulatory-accepted primary endpoint in this disease state, it is not a validated surrogate for overall survival for this novel therapeutic strategy, as the intervention could theoretically impact postprogression survival. A further limitation is the potential for conventional imaging to misinterpret early changes during BAT as true disease progression. The imaging schedule (every 8 wk), while aligned with prior BAT trials for comparability, may not fully capture transient "flare" phenomena that could precede a response to subsequent intermittent darolutamide. Finally, the optimal duration for cycling of BAT and darolutamide is unknown. According to prior experience, a return to castrate testosterone levels can take up to four half-lives (∼28-36 d). Therefore, a limitation of the study is that each 56-d cycle may be insufficient to induce maximum and durable resensitization to darolutamide before subsequent testosterone administration. FUNDING: WOMBAT is funded by a grant from Bayer to ANZUP. ANZUP also receives infrastructure funding from the Australian Government via Cancer Australia. ETHICS AND TRIAL REGISTRATION: The trial has been approved by the ethics committee of St. Vincent's Hospital Sydney and is registered on ANZCTR (ACTRN12624000582550) and ClinicalTrials.gov (NCT06594926). PATIENT SUMMARY: Men with prostate cancer that is no longer controlled by standard hormone therapies are at risk of cancer progression. This study will test an experimental treatment called bipolar androgen therapy (BAT). BAT uses high-dose testosterone in cycles to see if it can resensitize the cancer cells to treatment and delay the spread of cancer to other parts of the body. CLINICAL TRIAL IN CONTEXT: Resistance to androgen receptor pathway inhibitors (ARPIs) such as darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC) signals impending metastatic progression, so there is a clinical unmet need in this setting. Although bipolar androgen therapy (BAT) can resensitize tumors to ARPIs in metastatic CRPC, its efficacy in preventing or delaying metastasis in nmCRPC has not yet been evaluated. WOMBAT is a prospective, multicenter, single-arm, phase 2 study enrolling ∼69 participants with nmCRPC experiencing biochemical progression on darolutamide. Participants receive treatment comprising high-dose intramuscular testosterone (BAT) followed by intermittent darolutamide, maintained on a backbone of continuous androgen deprivation therapy in 56-d cycles. The primary endpoint is metastasis-free survival. This trial is investigating a novel strategy to extend the darolutamide therapeutic window and delay metastasis by resensitizing cancer cells to androgen receptor inhibition. Uniquely, cyclical administration of supraphysiologic testosterone has the potential to alleviate the cumulative toxicity of long-term castration and thus to offer improvements in health-related quality of life and bone mineral density. As the first study to investigate BAT in nmCRPC, WOMBAT could establish a new treatment paradigm for darolutamide-refractory disease.