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Observational Study
. 2024 May;35(5):458-472.
doi: 10.1016/j.annonc.2024.01.011. Epub 2024 Feb 27.

Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes

D Olmos  1 , D Lorente  2 , D Alameda  3 , C Cattrini  4 , N Romero-Laorden  5 , R Lozano  6 , P P Lopez-Casas  7 , A Jambrina  7 , C Capone  8 , A M Vanden Broecke  9 , M Trevisan  10 , S Van Sanden  11 , A Jürgens  12 , B Herrera-Imbroda  13 , E Castro  14
Affiliations
Free article
Observational Study

Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes

D Olmos et al. Ann Oncol. 2024 May.
Free article

Abstract

Background: Although germline BRCA mutations have been associated with adverse outcomes in prostate cancer (PC), understanding of the association between somatic/germline alterations in homologous recombination repair (HRR) genes and treatment outcomes in metastatic castration-resistant PC (mCRPC) is limited. The aim of this study was to investigate the prevalence and outcomes associated with somatic/germline HRR alterations, particularly BRCA1/2, in patients initiating first-line (1L) mCRPC treatment with androgen receptor signalling inhibitors (ARSi) or taxanes.

Patients and methods: Data from 729 mCRPC patients were pooled for CAPTURE from four multicentre observational studies. Eligibility required 1L treatment with ARSi or taxanes, adequate tumour samples and biomarker panel results. Patients underwent paired normal and tumour DNA analyses by next-generation sequencing using a custom gene panel including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B and RAD54L. Patients were divided into subgroups based on somatic/germline alteration(s): with BRCA1/2 mutations (BRCA); with HRR mutations except BRCA1/2 (HRR non-BRCA); and without HRR alterations (non-HRR). Patients without BRCA1/2 mutations were classified as non-BRCA. Radiographic progression-free survival (rPFS), progression-free survival 2 (PFS2) and overall survival (OS) were assessed.

Results: Of 729 patients, 96 (13.2%), 127 (17.4%) and 506 (69.4%) were in the BRCA, HRR non-BRCA and non-HRR subgroups, respectively. BRCA patients performed significantly worse for all outcomes than non-HRR or non-BRCA patients (P < 0.05), while PFS2 and OS were significantly shorter for BRCA than HRR non-BRCA patients (P < 0.05). HRR non-BRCA patients also had significantly worse rPFS, PFS2 and OS than non-HRR patients. Exploratory analyses suggested that for BRCA patients, there were no significant differences in outcomes associated with 1L treatment choice (ARSi or taxanes) or with the somatic/germline origin of the alterations.

Conclusions: Worse outcomes were observed for mCRPC patients in the BRCA subgroup compared with non-BRCA subgroups, either HRR non-BRCA or non-HRR. Despite its heterogeneity, the HRR non-BRCA subgroup presented worse outcomes than the non-HRR subgroup. Screening early for HRR mutations, especially BRCA1/2, is crucial in improving mCRPC patient prognosis.

Keywords: breast cancer genes 1/2; homologous recombination repair mutations; overall survival; prostate cancer.

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Conflict of interest statement

Disclosure DO: consulting/advisory role for AstraZeneca, Bayer, Clovis Oncology, Daiichi-Sankyo, Janssen and MSD Oncology; travel/accommodations/expenses from AstraZeneca Spain, Bayer, Ipsen, Janssen and Roche; honoraria from AstraZeneca, Bayer, Janssen, Pfizer and MSD; and research funding from AstraZeneca, Bayer, Genentech/Roche, Janssen, MSD Oncology and Pfizer. DL: consulting/advisory role for AstraZeneca, Bristol-Myers Squibb, Janssen Oncology and Pfizer; speakers’ bureau for Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, Janssen Oncology, Merck/Pfizer and Roche; and travel/accommodations/expenses from Astellas Pharma, AstraZeneca and Janssen Oncology. CC: consulting/advisory role for AstraZeneca, Janssen and MSD; travel/accommodations/expenses from Bayer, Bristol-Myers Squibb, Ipsen, Janssen and MSD; and research funding from Gilead Sciences. NRL: consulting/advisory role for AstraZeneca, Clovis Oncology, GlaxoSmithKline, Janssen and MSD; and research funding from Janssen-Cilag, MSD and Pfizer. RL: consulting/advisory role for Advanced Accelerator Applications, Janssen Oncology, Merck/Pfizer and Orion; travel/accommodations/expenses from Astellas Pharma, Bristol-Myers Squibb/Pfizer, Ipsen, Janssen, Merck, MSD, Roche and Sanofi; and honoraria from Astellas Pharma, Bayer, Janssen, Roche and Sanofi. CaC, AMVB, MT and AlJ: employees of Janssen. SVS: employee of, received travel/accommodations/expenses from and has stock and other ownership interests in Janssen. EC: consulting/advisory role for Astellas Pharma, AstraZeneca, Bayer, Daiichi-Sankyo, Janssen, Lilly, Medscape, Merck, MSD Oncology and Pfizer; speakers’ bureau from AstraZeneca, Janssen, Novartis and Pfizer; travel/accommodations/expenses from AstraZeneca, Bayer, Janssen and Pfizer; honoraria from Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Medscape, Pfizer, Roche and Telix; and research funding from AstraZeneca, Bayer and Janssen. All other authors have declared no conflicts of interest.

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