A recent multicenter, open-label Phase 2b trial investigated the optimal treatment approach for patients with poor-prognosis metastatic castration-resistant prostate cancer (mCRPC) who progressed after docetaxel chemotherapy. The study compared the clinical efficacy of cabazitaxel chemotherapy versus androgen receptor pathway inhibitors (ARPIs), specifically abiraterone plus prednisone or enzalutamide, in this challenging treatment-refractory population. Additionally, it explored the prognostic and predictive utility of circulating tumor DNA (ctDNA) analysis to help guide individualized therapy.

A total of 106 mCRPC patients with poor prognostic features were randomized to receive either cabazitaxel (25 mg/m² every three weeks with daily prednisone) or an ARPI (1000 mg abiraterone plus prednisone or 160 mg enzalutamide daily). The trial’s primary endpoint was clinical benefit rate (CBR) at 12 weeks, with secondary endpoints including radiographic progression-free survival (rPFS), overall survival (OS), and PSA50 response (≥50% decline in PSA levels). Genomic characterization of plasma ctDNA was performed at baseline, 12 weeks, and progression to investigate biomarkers related to prognosis and treatment response.

The trial revealed no statistically significant difference in the 12-week clinical benefit rate between the cabazitaxel and ARPI arms, with an overall CBR of 62.3%. Median follow-up of 30.9 months showed that radiographic progression-free survival and overall survival outcomes were comparable across both treatment groups. Interestingly, the PSA50 response rate was higher in the ARPI group at 47.2% compared to 26.9% in the cabazitaxel group.

Prior exposure to ARPIs, present in 37.7% of patients, was associated with significantly worse outcomes when treated again with ARPIs but did not affect response to cabazitaxel. Adverse events of Grade 3 or higher were more frequent with cabazitaxel, affecting 65.4% of patients versus 30.2% in the ARPI cohort.

Baseline ctDNA fraction emerged as a powerful prognostic biomarker, with higher ctDNA levels correlating with shorter progression-free and overall survival. Though plasma androgen receptor copy number status did not predict outcomes, alterations in the tumor suppressor gene PTEN were significantly linked to decreased survival (hazard ratio 1.9). These findings emphasize the potential role of ctDNA and genomic profiling in stratifying risk and guiding personalized treatment decisions.

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