A Randomized Phase II study of androgen deprivation therapy with or without palbociclib in RB-positive metastatic hormone-sensitive prostate cancer

Phillip L. Palmbos, Stephanie Daignault-Newton, Scott A. Tomlins, Neeraj Agarwal, Przemyslaw Twardowski, Alicia K. Morgans, Wm Kevin Kelly, Vivek K. Arora, Emmanuel S. Antonarakis, Javed Siddiqui, Jon A. Jacobson, Matthew S. Davenport, Dan R. Robinson, Arul M. Chinnaiyan, Karen E. Knudsen, Maha Hussain

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Purpose: Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, blocks proliferation in a RB and cyclin D-dependent manner in preclinical prostate cancer models. We hypothesized that cotargeting androgen receptor and cell cycle with palbociclib would improve outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Patients and Methods: A total of 60 patients with RB-intact mHSPC were randomized (1:2) to Arm 1: androgen deprivation (AD) or Arm 2: AD þ palbociclib. Primary endpoint was PSA response rate (RR) after 28 weeks of therapy. Secondary endpoints included safety, PSA, and clinical progression-free survival (PFS), as well as PSA and radiographic RR. Tumors underwent exome sequencing when available. Circulating tumor cells (CTC) were enumerated at various timepoints. Results: A total of 72 patients with mHSPC underwent metastatic disease biopsy and 64 had adequate tissue for RB assessment. A total of 62 of 64 (97%) retained RB expression. A total of 60 patients initiated therapy (Arm 1: 20; Arm 2: 40). Neutropenia was the most common grade 3/4 adverse event in Arm 2. Eighty percent of patients (Arm 1: 16/20, Arm 2: 32/40; P ¼ 0.87) met primary PSA endpoint ≤4 ng/mL at 28 weeks. PSA undetectable rate at 28 weeks was 50% and 43% in Arms 1 and 2, respectively (P ¼ 0.5). Radiographic RR was 89% in both arms. Twelve-month biochemical PFS was 69% and 74% in Arms 1 and 2, respectively (P ¼ 0.72). TP53 and PIK3 pathway mutations, 8q gains, and pretreatment CTCs were associated with reduced PSA PFS. Conclusions: Palbociclib did not impact outcome in RB-intact mHSPC. Pretreatment CTC, TP53 and PIK3 pathway mutations, and 8q gain were associated with poor outcome.

Original languageEnglish (US)
Pages (from-to)3017-3027
Number of pages11
JournalClinical Cancer Research
Issue number11
StatePublished - Jun 1 2021
Externally publishedYes

Bibliographical note

Funding Information:
This work was funded by grants from Pfizer, Movember-PCF Challenge (to M. Hussain), NIH K08 CA201335 (to P.L. Palmbos), and EDRN U01CA214170 and SPORE P50 CA186786 (to J. Siddiqui). The authors would like to thank the patients and their families for participation in this study. Clinical Trial Registration: NCT02059213.

Funding Information:
P.L. Palmbos reports grants from Pfizer and Prostate Cancer Foundation during the conduct of the study, as well as other from Immunomedics and F. Hoffmann-La Roche Ltd outside the submitted work. S. Daignault-Newton reports other from Pfizer during the conduct of the study, as well as personal fees from American Urological Association outside the submitted work. S.A. Tomlins reports nonfinancial support from Ventana/Roche during the conduct of the study, as well as personal fees and other from Strata Oncology and grants and personal fees from Astellas outside the submitted work; in addition, S.A. Tomlins has a patent for ETS gene fusions in prostate cancer issued, licensed, and with royalties paid from Ventana/Roche, Hologic/GenProbe, and LynxDX. N. Agarwal reports personal fees from and reports consultancy with Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics during the conduct of the study. A.K. Morgans reports personal fees from Astellas, AstraZeneca, Advanced Accelerator Applications, Clovis, Dendreon, Blue Earth, Janssen, and Pfizer;

Publisher Copyright:
© 2021 American Association for Cancer Research.

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