Phase 1b/2 Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer

Abstract Purpose: To report efficacy and safety of samotolisib (LY3023414; phosphoinositide 3- kinase/mechanistic target of rapamycin [PI3K/mTOR] dual kinase and DNA-dependent protein kinase [DNA-PK] inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone. Patients and Methods: In this double-blind, placebo-controlled phase 1b/2 study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, advanced CRPC patients with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences. Results: Overall, 13 and 129 patients were enrolled in phase 1b and 2, respectively. Dose limiting toxicity was not reported in patients during phase 1b and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase 2, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide vs placebo/enzalutamide arm (3.8 vs 2.8 months; P = 0.003) and (10.2 vs 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide vs placebo/enzalutamide arm (13.2 months vs 5.3 months; P = 0.03). Conclusions: Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone and this may be enriched in patients with PTEN intact and no AR-v7.