Inherited mutations in DNA repair genes in men with metastatic castration-resistant prostate cancer.

140 Background: Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to Androgen Receptor (AR) targeted therapy. The aim of this study was to determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies, and secondly to establish whether biallelic DNA-repair gene loss is detectable in matched circulating tumor DNA (ctDNA). Methods: We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In affected patients, matched plasma ctDNA was also sequenced. Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis. Results: 24/319 (7.5%) patients had deleterious germline mutations, with BRCA2 (n = 16), PALB2 (n = 2) and CDK12 (n = 2) being the most frequent. Patients (n = 22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but after starting ADT progressed to mCRPC with a median time of 12.3 months (95% CI 5.1-18.4). The median time to progression on first and second line AR-targeted therapy in the mCRPC setting was 3.2 months (95% CI 1.9-4.4) and 1.0 month (95% CI 0.8-1.1), respectively. For patients receiving chemotherapy as their initial therapy for mCRPC (n = 8) the median PFS was 7.5 months (95% CI 6.5-8.2). 10/11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. Conclusions: mCRPC patients with germline DNA repair defects exhibit transient responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.

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Reply to Johann S. de Bono, Maha Hussain, and Jinyu Kang’s Letter to the Editor re: Konrad H. Stopsack. Efficacy of PARP Inhibition in Metastatic Castration-resistant Prostate Cancer is Very Different with Non-BRCA DNA Repair Alterations: Reconstructing Prespecified Endpoints for Cohort B from the Phase 3 PROfound Trial of Olaparib. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2020.09.024

European Urology ◽

10.1016/j.eururo.2020.12.018 ◽

2020 ◽

Author(s):

Konrad H. Stopsack

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Parp Inhibition ◽

Castration Resistant Prostate Cancer ◽

Phase 3 ◽

Castration Resistant ◽

Letter To The Editor

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Changing the History of Prostate Cancer with New Targeted Therapies

Biomedicines ◽

10.3390/biomedicines9040392 ◽

2021 ◽

Vol 9 (4) ◽

pp. 392

Author(s):

Susana Hernando Polo ◽

Diana Moreno Muñoz ◽

Adriana Carolina Rosero Rodríguez ◽

Jorge Silva Ruiz ◽

Diana Isabel Rosero Rodríguez ◽

...

Keyword(s):

Prostate Cancer ◽

Targeted Therapies ◽

Synthetic Lethality ◽

Castration Resistant Prostate Cancer ◽

Phosphatidylinositol 3 Kinase ◽

Castration Resistant ◽

Therapeutic Landscape ◽

Important Benefit ◽

History Of ◽

Repair Genes

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is changing due to the emergence of new targeted therapies for the treatment of different molecular subtypes. Some biomarkers are described as potential molecular targets different from classic androgen receptors (AR). Approximately 20–25% of mCRPCs have somatic or germline alterations in DNA repair genes involved in homologous recombination. These subtypes are usually associated with more aggressive disease. Inhibitors of the enzyme poly ADP ribose polymerase (PARPi) have demonstrated an important benefit in the treatment of these subtypes of tumors. However, tumors that resistant to PARPi and wildtype BRCA tumors do not benefit from these therapies. Recent studies are exploring drug combinations with phosphatidylinositol-3-kinase (PI3K) or protein kinase B (AKT) inhibitors, as mechanisms to overcome resistance or to induce BRCAness and synthetic lethality. This article reviews various different novel strategies to improve outcomes in patients with prostate cancer.

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Efficacy of PARP Inhibition in Metastatic Castration-resistant Prostate Cancer is Very Different with Non-BRCA DNA Repair Alterations: Reconstructing Prespecified Endpoints for Cohort B from the Phase 3 PROfound Trial of Olaparib

European Urology ◽

10.1016/j.eururo.2020.09.024 ◽

2020 ◽

Author(s):

Konrad H. Stopsack

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Parp Inhibition ◽

Castration Resistant Prostate Cancer ◽

Phase 3 ◽

Castration Resistant

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Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djaa132 ◽

2020 ◽

Cited By ~ 1

Author(s):

Burcu F Darst ◽

Tokhir Dadaev ◽

Ed Saunders ◽

Xin Sheng ◽

Peggy Wan ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Statistical Tests ◽

European Ancestry ◽

International Studies ◽

Dna Repair Genes ◽

Variant Gene ◽

Significant Gene ◽

Repair Genes

Abstract Background There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease. Methods Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided. Results BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4). Conclusions Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.

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