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Assessing olaparib efficacy in U.S. Veterans with metastatic prostate cancer utilizing a time-indifferent g-rate method ideal for real-world analyses.
Leuva, Harshraj; Zhou, Mengxi; Jamaleddine, Nader; Meseha, Mina; Faiena, Izak; Anna Park, Yeun-Hee; McWilliams, Glen; Luhrs, Carol; Maxwell, Kara N; Von Hoff, Daniel; Bates, Susan E; Fojo, Tito.
Afiliação
  • Leuva H; University of Nebraska Medical Center, Omaha, NE, USA; James J. Peters Bronx Veterans Affairs Medical Center, Bronx, NY, USA. Electronic address: hleuva@unmc.edu.
  • Zhou M; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA.
  • Jamaleddine N; SUNY Downstate Health Sciences University, Brooklyn, NY, USA; Veterans Affairs New York Harbor Healthcare System - Brooklyn Campus, NY, USA.
  • Meseha M; SUNY Downstate Health Sciences University, Brooklyn, NY, USA; Veterans Affairs New York Harbor Healthcare System - Brooklyn Campus, NY, USA.
  • Faiena I; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA; James J. Peters Bronx Veterans Affairs Medical Center, Bronx, NY, USA.
  • Anna Park YH; James J. Peters Bronx Veterans Affairs Medical Center, Bronx, NY, USA.
  • McWilliams G; James J. Peters Bronx Veterans Affairs Medical Center, Bronx, NY, USA.
  • Luhrs C; SUNY Downstate Health Sciences University, Brooklyn, NY, USA; Veterans Affairs New York Harbor Healthcare System - Brooklyn Campus, NY, USA.
  • Maxwell KN; Medicine and Genetics, Penn Medicine, and Corporal Michael Crescenz VAMC, USA.
  • Von Hoff D; Translational Genomics Research Institute, and HonorHealth Clinical Research Institute, Phoenix, AZ, USA.
  • Bates SE; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA; James J. Peters Bronx Veterans Affairs Medical Center, Bronx, NY, USA.
  • Fojo T; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA; James J. Peters Bronx Veterans Affairs Medical Center, Bronx, NY, USA. Electronic address: atf2116@cumc.columbia.edu.
EBioMedicine ; 107: 105288, 2024 Sep.
Article em En | MEDLINE | ID: mdl-39180789
ABSTRACT

BACKGROUND:

We aimed to assess real-world efficacy of the PARP inhibitor, olaparib, in US Veterans with metastatic prostate cancer (mPC) by leveraging the national data repository and evaluate a novel approach to assess treatment efficacy in tumors considered rare or harboring rare mutations.

METHODS:

Included Veterans had 1) mPC with somatic or germline alterations/mutations in genes involved in homologous recombination repair (HRR), 2) received olaparib monotherapy as well as a novel hormonal therapy/androgen receptor pathway inhibitors (NHT/ARPI), and/or chemotherapy, and 3) estimable rates of tumor growth (g-rate) using PSA values obtained while receiving treatment. Previous work has shown an excellent inverse correlation of g-rate with survival. Using g-rate, we determined tumor doubling time (DT) and DT ratios (DT on olaparib/DT on prior medication). We postulated that a DT ratio≥ 1 was associated with benefit.

FINDINGS:

We identified 139 Veterans, including 42 Black males with tumors harboring mutations/alterations in HRR genes who received olaparib BRCA2 (50), ATM (32), BRCA1 (10), other mutations (47). 62/139 (45%) of all and 21/42 (50%) of Black Veterans had DT ratios ≥1, including 31, 10, 2, and 19 with BRCA2, ATM, BRCA1, and other mutations, respectively (p = 0.006). Median survival with DT ratios ≥1 was superior, being 24.5 vs. 11.4 months for DT ratio <1 (p = 0.01, HR 0.50, 95% CI 0.29-0.85). Benefit from olaparib, defined as DT ratio ≥1, was not observed for germline status, starting PSA value, number of prior therapies, or immediate prior therapy. Compared to matched cohorts, tumors in the olaparib cohort had shorter DTs with enzalutamide in first line (367 vs. 884 days; p = 0.0043).

INTERPRETATION:

Using equations indifferent to timing of assessments ideal for real-world efficacy analyses, we showed DT ratio ≥1 representing slower tumor growth on olaparib relative to the prior therapy correlates with improved survival. Olaparib efficacy in Veterans with mPC harboring mutations/alterations in HRR genes emulates clinical trial results. Black men had comparable results. Compared to matched cohorts, in first line, enzalutamide was less efficacious in tumors harboring mutations/alterations in HRR genes.

FUNDING:

American Society of Clinical Oncology Conquer Cancer Foundation (ASCO CCF), the Blavatnik Family Foundation and the Prostate Cancer Foundation (PCF).
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ftalazinas / Piperazinas / Neoplasias da Próstata / Veteranos / Inibidores de Poli(ADP-Ribose) Polimerases Limite: Aged / Aged80 / Humans / Male / Middle aged País/Região como assunto: America do norte Idioma: En Revista: EBioMedicine Ano de publicação: 2024 Tipo de documento: Article País de publicação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ftalazinas / Piperazinas / Neoplasias da Próstata / Veteranos / Inibidores de Poli(ADP-Ribose) Polimerases Limite: Aged / Aged80 / Humans / Male / Middle aged País/Região como assunto: America do norte Idioma: En Revista: EBioMedicine Ano de publicação: 2024 Tipo de documento: Article País de publicação: Holanda