A Phase Ib/II Study of the CDK4/6 Inhibitor Ribociclib in Combination with Docetaxel plus Prednisone in Metastatic Castration-Resistant Prostate Cancer

Ivan de Kouchkovsky, Arpit Rao, Benedito A. Carneiro, Li Zhang, Catriona Lewis, Audrey Phone, Eric J. Small, Terence Friedlander, Lawrence Fong, Pamela L. Paris, Charles J. Ryan, Russell Z. Szmulewitz, Rahul Aggarwal

Ribociclib, a CDK4/6 inhibitor, demonstrates pre-clinical anti-tumor activity in combination with taxanes. We evaluated the safety and efficacy of ribociclib plus docetaxel in a phase Ib/II study in metastatic castration-resistant prostate cancer (mCRPC). Patients had chemotherapy-naive mCRPC with progression on {greater than or equal to} 1 androgen receptor signaling inhibitor (ARSI). The phase II primary endpoint was 6-month radiographic progression-free survival (rPFS) rate, with an alternative hypothesis of 55% versus 35% historical control. Circulating tumor cells (CTC) were collected at baseline and genomically profiled. Forty-three patients were enrolled (N = 30 in Phase II). Two dose-limiting toxicities were observed (Grade 4 neutropenia and febrile neutropenia). The recommended phase 2 dose (RP2D) and schedule was docetaxel 60 mg/m2 every 21 days plus ribociclib 400 mg/day on days 1-4 and 8-15 with filgrastim on days 5-7. At the RP2D, neutropenia was the most common grade {greater than or equal to} 3 adverse event (37%); however, no cases of febrile neutropenia were observed. The primary endpoint was met; the 6-month rPFS rate was 65.8% (95% CI: 50.6% - 85.5%; p = 0.005) and median rPFS was 8.1 months (95% CI: 6.0 - 10.0 months). 32% of evaluable patients achieved a PSA50 response. Non-amplified <em>MYC </em>in baseline CTCs was associated with longer rPFS (p = 0.052). The combination of intermittent ribociclib plus every 3-week docetaxel demonstrated acceptable toxicity and encouraging efficacy in ARSI-pretreated mCRPC. Genomic profiling of CTCs may enrich for those most likely to derive benefit. Further evaluation in a randomized clinical trial is warranted.