Summary of the PC-BETS Substudy C: Darolutamide in Biomarker-Selected mCRPC
The Canadian Cancer Trials Group’s phase II PC-BETS umbrella trial, conducted through the Vancouver Prostate Centre, screened nearly 600 patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor DNA (ctDNA) to identify actionable genomic alterations.
Substudy C, presented at ASCO 2025, evaluated darolutamide (600 mg twice daily) in 57 patients with androgen receptor (AR) alterations,29 with AR gain and 28 with AR mutations (e.g., T878A, L702H), after progression on prior AR pathway inhibitors (ARPIs) like abiraterone or enzalutamide, but excluding prior docetaxel.
The rationale was darolutamide’s unique structure, which preclinical studies suggested could overcome ARPI resistance due to AR amplification or ligand-binding domain mutations. The primary endpoint, clinical benefit rate (CBR: PSA decline ≥50%, RECIST complete/partial response, or stable disease ≥12 weeks), showed modest responses, comparable to other ARPI-to-ARPI switches.
Patients with AR copy number >10 exhibited some enriched benefit, but overall activity was not robust enough to alter clinical practice.
The study highlights the feasibility of ctDNA-driven precision oncology and the challenges of targeting AR alterations in heavily pretreated mCRPC, emphasizing the need for more potent therapies in this setting.