A Randomized Phase II Study of Androgen Deprivation Therapy with or without Palbociclib in RB-positive Metastatic Hormone-Sensitive Prostate Cancer.


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).

A total of 60 patients with RB-intact mHSPC were randomized (1:2) to Arm 1: androgen deprivation (AD) or Arm 2: AD + 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.

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; <i>P</i> = 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 (<i>P</i> = 0.5). Radiographic RR was 89% in both arms. Twelve-month biochemical PFS was 69% and 74% in Arms 1 and 2, respectively (<i>P</i> = 0.72). TP53 and PIK3 pathway mutations, 8q gains, and pretreatment CTCs were associated with reduced PSA PFS.

Palbociclib did not impact outcome in RB-intact mHSPC. Pretreatment CTC, TP53 and PIK3 pathway mutations, and 8q gain were associated with poor outcome.

  • Agarwal N
  • Antonarakis ES
  • Arora VK
  • Chinnaiyan AM
  • Daignault-Newton S
  • Davenport MS
  • Hussain M
  • Jacobson JA
  • Kelly WK
  • Knudsen KE
  • Morgans AK
  • Palmbos PL
  • Robinson DR
  • Siddiqui J
  • Tomlins SA
  • Twardowski P
PubMed ID
Appears In
Clin Cancer Res, 2021, 27 (11)