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

Autor: Phillip L. Palmbos, Przemyslaw Twardowski, Vivek K. Arora, Alicia K. Morgans, Dan R. Robinson, Karen E. Knudsen, Matthew S. Davenport, Maha Hussain, Neeraj Agarwal, Javed Siddiqui, Emmanuel S. Antonarakis, Jon A. Jacobson, Stephanie Daignault-Newton, Scott A. Tomlins, Wm. Kevin Kelly, Arul M. Chinnaiyan
Rok vydání: 2021
Předmět:
Adult
Male
0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
Pyridines
Phases of clinical research
Bone Neoplasms
Soft Tissue Neoplasms
Neutropenia
Palbociclib
Retinoblastoma Protein
Disease-Free Survival
Piperazines
Article
Androgen deprivation therapy
Phosphatidylinositol 3-Kinases
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Circulating tumor cell
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Biopsy
medicine
Clinical endpoint
Humans
Aged
Aged
80 and over
medicine.diagnostic_test
business.industry
Prostatic Neoplasms
Androgen Antagonists
Middle Aged
Neoplastic Cells
Circulating
medicine.disease
Treatment Outcome
030104 developmental biology
030220 oncology & carcinogenesis
Mutation
Tumor Suppressor Protein p53
business
Signal Transduction
Zdroj: Clin Cancer Res
ISSN: 1557-3265
1078-0432
Popis: 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.
Databáze: OpenAIRE
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