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Published on: March 6, 2018
A Randomized Phase II Study of Androgen Deprivation Therapy with or without Palbociclib in RB-positive Metastatic
Phillip L Palmbos1, Stephanie Daignault-Newton1, Scott A Tomlins1
1Michigan Medicine Rogel Cancer Center, Ann Arbor, Michigan.
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.
Insights
Adding palbociclib to androgen deprivation therapy did not improve outcomes for patients with metastatic hormone-sensitive prostate cancer. Biomarkers like circulating tumor cells and specific gene mutations predicted poorer outcomes in this prostate cancer study.
Area of Science:
- Oncology
- Prostate Cancer Research
- Cell Cycle Inhibitors
Background:
- Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor that blocks proliferation in preclinical prostate cancer models.
- The study aimed to evaluate if combining androgen receptor and cell cycle inhibition could improve outcomes in metastatic hormone-sensitive prostate cancer (mHSPC).
Purpose of the Study:
- To assess the efficacy of adding palbociclib to androgen deprivation (AD) therapy in patients with RB-intact mHSPC.
- To identify predictive biomarkers for treatment response and progression.
Main Methods:
- A randomized trial involving 60 patients with RB-intact mHSPC, comparing AD alone versus AD plus palbociclib.
- Primary endpoint was prostate-specific antigen (PSA) response rate at 28 weeks; secondary endpoints included safety, progression-free survival (PFS), and radiographic response.
- Tumor exome sequencing and circulating tumor cell (CTC) enumeration were performed.
Main Results:
- No significant difference in PSA response rate (80% in both arms) or PSA undetectable rates at 28 weeks between the two arms.
- Radiographic response rates (89%) and 12-month biochemical PFS (69% vs 74%) were similar in both groups.
- Neutropenia was the most common grade 3/4 adverse event in the palbociclib arm.
- Pretreatment CTCs, TP53 and PIK3 pathway mutations, and 8q gains were associated with reduced PSA PFS.
Conclusions:
- Palbociclib did not improve outcomes in patients with RB-intact mHSPC when added to AD therapy.
- Biomarkers including pretreatment CTCs, TP53 and PIK3 pathway mutations, and 8q gain are associated with poor outcomes in mHSPC.
