Global Real‐World Outcomes of Olaparib in Metastatic Castration‐Resistant Prostate Cancer Patients With Homologous Recombination Repair Alterations

Evidence to guide the treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) and Homologous Recombination Repair (HRR) gene alterations outside of clinical trials remains limited. This was an observational, cohort study, including mCRPC patients with tumor harboring HRR alterations, progressed on a prior androgen receptor pathway inhibitor, and treated with olaparib monotherapy from January 1, 2020, to April 30, 2025. Primary objectives were time on treatment (ToT) and overall survival (OS). Secondary objective was to explore the role of gene and type and location of pathogenic variant (PVs) as potential molecular predictors of olaparib benefit. We included 201 patients in the analysis. No significant differences in OS across distinct HRR gene subgroups were observed (median OS BRCA1/2 vs. non-BRCA HRR: 16.3 months [95% CI, 13.0-69.6] vs. 14.2 [95% CI, 12.0-22.9; p = 0.681]). Primary refractoriness to olaparib occurred in 36 (18%) patients and was associated with poor survival (1 year-OS rate of primary vs. non-primary refractory: 20% vs. 77%; p < 0.001). The 1 year-ToT rate of BRCA1 versus BRCA2 was 23% versus 39%, respectively (p = 0.021). Frameshift PVs in the BRCA2 gene were a prognostic factor for shorter OS. Differences in OS according to the PV location in the BRCA2 functional domains were also significant. Olaparib demonstrated clinical activity in this global, real world, population of mCRPC patients with HRR-altered tumors. Accurately detecting the multitude of variables associated with BRCA genetic variants represents a key area of research potentially affecting the patient's clinical outcomes.

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Journal
International Journal of Cancer
Published
2026-08-18
DOI
https://doi.org/10.1002/ijc.70679
Primary Topic
Prostate Cancer Treatment and Research
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article
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article

Global Real‐World Outcomes of Olaparib in Metastatic Castration‐Resistant Prostate Cancer Patients With Homologous Recombination Repair Alterations

Lorenzo Antonuzzo, Massimo Di Maïo, Tancredi Didier Bazan Russo, M. Puglisi et al.
International Journal of Cancer
Prostate Cancer Treatment and Research
article

Global Real‐World Outcomes of Olaparib in Metastatic Castration‐Resistant Prostate Cancer Patients With Homologous Recombination Repair Alterations

Lorenzo Antonuzzo, Massimo Di Maïo, Tancredi Didier Bazan Russo, M. Puglisi, Ilaria Depetris, Marco Stellato, Thomas Büttner, Giulia Mammone, Vincenza Conteduca, Sabrina Rossetti, Lorena Incorvaia, Camila Bobato Lara Gismondi, Sergio Bracarda, Martin Ignacio Zapata Laguado, Francesco Massari, Yüksel Ürün, Fernando Sabino Marques Monteiro, Nicola Pavan, Deniz Güncel Tural, Brigida Anna Maiorano, Isadora Yasbick Spricido, Carlo Messina, Maite Bourlon, Ray Manneh Kopp, Tarek Taha, Marc R. MATRANA, Giuseppe Procopio, Helga Lipari, Mimma Rizzo, Daniele Santini, Eleonora Lai, Alice Principi, Orazio Caffo, Marco Maruzzo, Andrey Soares, Matteo Santoni
article en

Abstract

Evidence to guide the treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) and Homologous Recombination Repair (HRR) gene alterations outside of clinical trials remains limited. This was an observational, cohort study, including mCRPC patients with tumor harboring HRR alterations, progressed on a prior androgen receptor pathway inhibitor, and treated with olaparib monotherapy from January 1, 2020, to April 30, 2025. Primary objectives were time on treatment (ToT) and overall survival (OS). Secondary objective was to explore the role of gene and type and location of pathogenic variant (PVs) as potential molecular predictors of olaparib benefit. We included 201 patients in the analysis. No significant differences in OS across distinct HRR gene subgroups were observed (median OS BRCA1/2 vs. non-BRCA HRR: 16.3 months [95% CI, 13.0-69.6] vs. 14.2 [95% CI, 12.0-22.9; p = 0.681]). Primary refractoriness to olaparib occurred in 36 (18%) patients and was associated with poor survival (1 year-OS rate of primary vs. non-primary refractory: 20% vs. 77%; p < 0.001). The 1 year-ToT rate of BRCA1 versus BRCA2 was 23% versus 39%, respectively (p = 0.021). Frameshift PVs in the BRCA2 gene were a prognostic factor for shorter OS. Differences in OS according to the PV location in the BRCA2 functional domains were also significant. Olaparib demonstrated clinical activity in this global, real world, population of mCRPC patients with HRR-altered tumors. Accurately detecting the multitude of variables associated with BRCA genetic variants represents a key area of research potentially affecting the patient's clinical outcomes.

International Journal of Cancer
University of Foggia (IT), Royal Marsden NHS Foundation Trust (GB), Koç University (TR), Vita-Salute San Raffaele University (IT), Universidad El Bosque (CO), University Hospital Bonn (DE), Ochsner Medical Center (US), Hospital Israelita Albert Einstein (BR), Policlinico Umberto I (IT), Popular University of Cesar (CO), Eastern Cooperative Oncology Group (US), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Ospedale Santa Chiara (IT), Ospedali Riuniti di Foggia (IT), Azienda Universitaria Ospedaliera Consorziale - Policlinico Bari (IT), Fondazione Ricerca Molinette (IT), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX), Istituto Oncologico Veneto (IT), Azienda Ospedaliero-Universitaria Careggi (IT), Azienda USL di Bologna (IT), Azienda Ospedaliera S.Maria (IT), Ospedale Cannizzaro (IT), Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT), Hospital Sírio-Libanês (BR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), Ospedale di Macerata, University of Macerata (IT), University of Palermo (IT), University of Bologna (IT)
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Openalex Percentile: Top 10%
Prostate Cancer Treatment and Research
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