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

Research output: Contribution to journalArticlepeer-review


Purpose: Ribociclib, a CDK4/6 inhibitor, demonstrates preclinical antitumor 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 and Methods: Patients had chemotherapy-naïve mCRPC with progression on ≥ 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. Result: 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 II dose (RP2D) and schedule was docetaxel 60 mg/m2every 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 ≥ 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% confidence interval (CI): 50.6%-85.5%; P = 0.005] and median rPFS was 8.1 months (95% CI, 6.0-10.0 months). Thirty-two percent of evaluable patients achieved a PSA50 response. Nonamplified MYC in baseline CTCs was associated with longer rPFS (P = 0.052). Conclusions: The combination of intermittent ribociclib plus every-3-weeks 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.

Original languageEnglish (US)
Pages (from-to)1531-1539
Number of pages9
JournalClinical Cancer Research
Issue number8
StatePublished - Apr 15 2022

Bibliographical note

Funding Information:
I. de Kouchkovsky reports grants from Novartis during the conduct of the study; grants from Conquer Cancer, the ASCO Foundation and grants from Prostate Cancer Foundation outside the submitted work. A. Rao reports grants from Novartis and Pfizer and grants and personal fees from Eisai and Eli Lilly and Company during the conduct of the study; other support from AstraZeneca; personal fees from Bayer, Sanofi, Cardinal Health, Bristol-Myers Squibb, Den-dreon Pharmaceuticals, Clovis Oncology, Pfizer/Astellas, and grants from Pfizer/ Seattle Genetics outside the submitted work. B.A. Carneiro reports other support from AstraZeneca, Astellas, Actuate Therapeutics, Pfizer, Dragonfly Therapeutics, Repare Therapeutcs, AbbVie, and MedImmune and personal fees from Foundation Medicine, Tempus, and Seagen, outside the submitted work. L. Zhang reports personal fees from Raydiant Oximetry Inc outside the submitted work. E.J. Small reports other support from Harpoon; grants and other support from Fortis and Teon; grants from Janssen, Johnson and Johnson; and grants from Ultragenyx during the conduct of the study; other support from Harpoon, personal fees and other support from Fortis, Teon; and personal fees from Janssen, Johnson and Johnson, and Ultragenyx outside the submitted work. T. Friedlander reports personal fees from EMD Serono, AstraZeneca, Astellas, AbbVie, Dendreon, Merck, Basilea, and Taiho outside the submitted work. L. Fong reports grants from AbbVie, Amgen, Bavarian Nordic, BMS, Dendreon, Janssen, Merck, and Roche/Genentech outside the submitted work. R.Z. Szmulewitz reports grants and personal fees from Pfizer and personal fees from Astellas, AstraZeneca, and Merck outside the submitted work. R. Aggarwal reports grants from Novartis during the conduct of the study; personal fees from AstraZeneca, Dendreon, Advanced Accelerator Applications, Exelixis Pfizer, and Jubilant Therapeutics and grants from Janssen, Merck Amgen outside the submitted work. No disclosures were reported by the other authors.

Funding Information:
A research grant to UCSF was provided by Novartis Pharmaceuticals. R. Aggarwal was supported by a Prostate Cancer Foundation Young Investigator Award (15YOUN02).

Publisher Copyright:
© 2022 American Association for Cancer Research Inc.. All rights reserved.

PubMed: MeSH publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Journal Article
  • Research Support, Non-U.S. Gov't


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