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.