We hypothesized that co-targeting AR and cell-cycle with palbociclib (a CDK4/6 inhibitor) would improve outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
60 patients with Rb-intact mHSPC were randomized (1:2) to Arm 1: androgen deprivation (AD) or Arm 2: AD+ palbociclib. The primary endpoint was PSA response rate (RR) after 28-weeks of therapy. Secondary endpoints included safety, PSA and clinical progression-free survival (PFS), PSA and radiographic RR. Tumors underwent exome sequencing when available. Circulating tumor cells (CTC) were enumerated at various time points.
72 patients with mHSPC underwent metastatic disease biopsy and 64 had adequate tissue for RB assessment. 62/64 (97%) retained RB expression. 60 patients initiated therapy (Arm 1: 20; Arm 2: 40). Neutropenia was the most common G3/4 adverse event in Arm 2. 80% of pts (Arm 1: 16/20, Arm 2: 32/40; p = 0.87) met primary PSA endpoint {less than or equal to}4ng/mL at 28 weeks. PSA undetectable rate at 28 weeks was 50% and 43% in Arms 1 and 2 respectively (p = 0.5). Radiographic RR was 89% in both arms. 12 month biochemical PFS was 69% and 74% in Arms 1 and 2, respectively (p=0.72). TP53, PIK3 pathway mutations, 8q gains, and pretreatment CTCs were associated with reduced PSA PFS.
Palbociclib did not impact the outcome in RB intact mHSPC. Pretreatment CTC, TP53, and PIK3 pathway mutations, and 8q gain were associated with poor outcome.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Mar 16 [Epub ahead of print]
Phillip L Palmbos, Stephanie Daignault-Newton, Scott A Tomlins, Neeraj Agarwal, Przemyslaw Twardowski, Alicia K Morgans, William K Kelly, Vivek K Arora, Emmanuel S Antonarakis, Javed Siddiqui, Jon Jacobson, Mathew S Davenport, Dan R Robinson, Arul M Chinnaiyan, Karen E Knudsen, Maha Hussain
Internal Medicine, University of Michigan–Ann Arbor., Urology, University of Michigan–Ann Arbor., Department of Pathology, Department of Urology, Michigan Center for Translational Pathology, Comprehensive Cancer Center, University of Michigan–Ann Arbor., Medicine, University of Utah/Huntsman Cancer Institute., John Wayne Cancer Institute., Medicine, Northwestern University., Medical Oncology, Thomas Jefferson University, Kimmel Cancer Center., Internal Medicine, Washington University in St. Louis., Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine., Pathology, University of Michigan–Ann Arbor., Radiology, University of Michigan–Ann Arbor., Department of Radiology, University of Michigan–Ann Arbor., Department of Pathology, University of Michigan–Ann Arbor., Depts of Cancer Biology, Urology, Medical Oncology, and Radiation Oncology, Sidney Kimmel Cancer Center at Jefferson Health., Hematology/Oncology, Northwestern University .