A randomized phase Ib/II study of enzalutamide (Enza) with and without ribociclib (Rib) in patients with metastatic castrate-resistant prostate cancer (mCRPC) that retains RB expression: RiboX study.

5057 Background: RB function is often attenuated in tumors through hyperphosphorylation; thus, RB activity can be “re-awakened” in RB+ tumors by suppressing key kinases that phosphorylate RB (CDK4/6). We report a phase Ib/II trial to determine the safety, tolerability and antitumor activity rib with enza in patients (pts) with mCRPC (NCT02555189). Methods: RiboX was a multicenter, phase Ib/II, open label trial which enrolled taxane-naïve pts with progression to mCRPC and retained RB expression. For phase Ib, a traditional 3x3 dose-escalation was used to establish the RP2D for the phase II portion. Pts received rib at 200, 400 or 600mg once daily (QD) Days (D) 1-21 in combination with fixed dose enza (160mg QD D1-28). In phase II, pts were randomized 1:1 to enza monotherapy (Arm A) or enza + rib (Arm B). The study was later modified to a single arm Simon two-stage design using the RP2D of 600mg rib with 160mg enza. The primary phase II endpoint was the proportion of pts a PSA50 response at 12 weeks. The null hypothesis was that the PSA50 response was ≤78% and 31 responses were required to reject the null hypothesis. Secondary endpoints were rPFS, PSA PFS, OS and safety. Results: 12 pts were enrolled in the phase Ib portion across three dose levels upon confirmation of RB expression on tumor biopsy. No DLTs were observed in dose-escalation and the RP2D was established at rib 600mg QD D 1-21 + enza 160mg QD D 1-28. The phase II portion included 12 pts treated with enza mono; 28 phase II pts and 6 phase 1b pts yielded 34 pts treated with combination at RP2D. The PSA50 response at 12 weeks was 75% (95% CI, 43-95) for enza mono and 82% (95% CI, 65-93) for the combination, failing to reject the null hypothesis. Median rPFS for evaluable pts was 10.9 mo (95% CI, 2.5-45.9) for enza mono (n = 12) and 27.0 mo (95% CI, 11.3-37.0) for combination (n = 30). PSA PFS was 10.1 months (95% CI, 1.8-33.1) for enza mono (n = 12) and 14.8 mo (95% CI, 6.7-35.9) for combination (n = 34). OS was 31.2 mo (95% CI, 15.0-NA) for enza mono (n = 12) and 58.1 mo (95% CI, 33.4-NA) for combination (n = 34). Four pts treated with combination were included for PSA PFS but did not have data for rPFS. Among pts treated at RP2D in the combination arm, the most common TEAE’s included fatigue 59%, nausea 26.9%, neutropenia 26.7% (grade 3, 12%), diarrhea 20.9%, dizziness 14.7%, arrhythmia 2.9%, seizure 2.9%. Conclusions: The combination of enza + rib was well tolerated; however, no significant difference in PSA50 response was observed, and the primary endpoint was not met. A disease-stabilizing effect was observed in a subset of patients treated with the enza + rib combination, with evidence of prolonged survival. Further investigation into this disease-stabilizing effect and refinement of patient selection criteria beyond RB expression may be warranted. Funding: Novartis Pharmaceuticals and DOD (W81XWH-22-2-0020). Clinical trial information: NCT02555189 .