Bristol Myers Squibb's investigational drug BMS-986365 has advanced to Phase 3 testing for metastatic castration-resistant prostate cancer (mCRPC), marking a significant milestone for this novel androgen receptor-targeting therapy that has shown promise in overcoming treatment resistance.
Phase 3 Trial Launches Globally
The rechARge trial (CA071-1000) is recruiting patients at 230 sites across 24 countries and territories in North America, Europe, Latin America, and East Asia. In Part 1 of the dose selection phase, patients are randomized 1:1:1 to receive either BMS-986365 at 400 or 300 mg twice daily every 28 days, or investigator's choice comprising androgen receptor pathway inhibitors (enzalutamide 160 mg daily or abiraterone 1000 mg daily plus prednisone) every 28 days, or docetaxel 75 mg/m² plus prednisone every 21 days for up to 10 cycles.
Secondary endpoints include safety, overall response rate, confirmed PSA response rate (PSA30 and PSA50), and patient reported outcomes, providing comprehensive assessment of the drug's therapeutic potential.
Encouraging Phase 1 Results Drive Development
Updated results from the first-in-human, multicenter study presented at the American Urology Association meeting showed promising outcomes. Data from Part B dose expansion included 68 patients treated at 400, 600, or 900 mg twice daily (20 patients each dose level).
"Treatment with BMS-986365 was well tolerated, with a manageable safety profile and promising anti-tumor activity," according to the study authors. "These data show the potential of BMS-986365 to overcome resistance to current ARPI (Androgen Receptor Pathway Inhibitors) in a large segment of patients regardless of AR genomic status."
Dr. Manish Patel from Florida Cancer Specialists & Research Institute, who presented the abstract, noted that "these insights equate to good news as we continue our work to improve survival rates for patients with advanced prostate cancer."
Novel Dual Mechanism of Action
BMS-986365 represents a new class of therapeutics known as androgen receptor ligand-directed degraders (AR LDD) with dual mechanism of action. The drug both degrades and inhibits the androgen receptor, potentially offering advantages over current standard-of-care treatments.
Preclinical studies demonstrated that BMS-986365 is approximately 100-fold more potent than enzalutamide at inhibiting androgen-stimulated transcription of AR target genes, and 10 to 120-fold more potent than enzalutamide at inhibiting AR-dependent proliferation of multiple prostate cancer cell lines in vitro.
Addressing Treatment Resistance
The majority of mCRPC remains androgen receptor-dependent even when resistant to current AR pathway inhibitors such as enzalutamide and abiraterone. BMS-986365 showed particular promise in heavily pretreated patients post-ARPI, with encouraging durability especially in patients with no prior chemotherapy.
The drug demonstrated activity regardless of AR genomic status, suggesting broad applicability across different patient populations. Treatment was well tolerated with no grade 4 adverse events reported, and patients experienced prolonged radiographic progression-free survival, particularly those without prior chemotherapy exposure.
Preclinical Validation Supports Clinical Development
Supporting preclinical data from CC2000199, a close analog of BMS-986365, showed significant tumor volume reductions in validated models of advanced castration-resistant prostate cancer and therapy-resistant patient-derived xenografts, including those with acquired resistance to enzalutamide. These models suggest that AR degraders may be superior to standard-of-care AR antagonists in disease-relevant animal models and enzalutamide-resistant mCRPC that remain dependent on androgen receptor signaling.
