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, 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

Abstract

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 + 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 = 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 = 0.5). Radiographic RR was 89% in both arms. Twelve-month biochemical PFS was 69% and 74% in Arms 1 and 2, respectively (P = 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.

Trial registration: ClinicalTrials.gov NCT02059213.

Conflict of interest statement

Conflict of Interest: Authors report no additional conflict of interest.

©2021 American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Study Schema.
Figure 2.
Figure 2.
Representative RB staining in metastatic prostate cancer biopsies. Left panels shown H&E stained tissues. Right panels demonstrate typical RB staining in metastatic prostate cancers with (bottom panel) and without RB loss (top panel).
Figure 3.
Figure 3.
Progression free survival. There were no statistically significant differences in biochemical PFS (A) or clinical PFS (B) between ADT and ADT + palbociclib arms.
Figure 4.
Figure 4.
Waterfall plot for radiographic response. Black bars = ADT + palbociclib. Gray bars = ADT alone. Metastatic lesion type is indicated across top of graph.
Figure 5.
Figure 5.
CTC correlative data. (A) Pretreatment CTC counts by patient and treatment arm. (B) Stratification of patients by pretreatment CTC (≥ 2 or

Figure 6.

Forrest Plot of Biochemical PFS…

Figure 6.

Forrest Plot of Biochemical PFS and association with mutation and CTC counts.

Figure 6.
Forrest Plot of Biochemical PFS and association with mutation and CTC counts.
Figure 6.
Figure 6.
Forrest Plot of Biochemical PFS and association with mutation and CTC counts.

Source: PubMed

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