The homologous recombination repair (HRR) pathway is a frequently mutated pathway in advanced prostate cancer. The clinical course of patients with HRR gene alterations who have metastatic hormone sensitive prostate cancer (mHSPC) has not been fully characterized. Here, we examine the outcomes of men with mHSPC with HRR alterations.
We conducted a single-center retrospective analysis of men with mHSPC who underwent next generation sequencing. The primary objective was to assess the time from diagnosis of mHSPC to metastatic castrate resistance prostate cancer (mCRPC) in patients with pathogenic HRR alterations compared to individuals lacking these alterations. Key secondary objectives included time to mCRPC in prespecified cohorts, PSA response, and overall survival.
151 men with mHSPC were identified for the study. 24% (N = 37) had pathogenic HRR gene alterations detected with the most common alterations found in BRCA2 (n = 15), ATM (n = 10), and CDK12 (n = 7). Time to mCRPC was significantly decreased in patients with HRR gene alterations versus those without such alterations (12.7 vs. 16.1 months, HR 1.95, P = .02). In multivariate analysis, the effect of HRR gene alterations on time to CRPC remained significant when adjusting for age, mHSPC therapy, the volume of disease, the presence of visceral metastases, and PSA (adjusted HR 1.69, P = .02). Stratified by specific HRR gene alteration, patients with BRCA2 or CDK12 had significantly decreased time to mCRPC compared to other HRR alterations.
HRR gene alterations are associated with the worse outcomes in mHSPC with significantly shorter time to mCRPC. Given the established role of Poly (ADP-ribose) Polymerase (PARP) inhibitors in mCRPC, these data highlight an opportunity to examine PARP inhibitors earlier in the clinical course for prostate cancer patients. Ongoing prospective studies will further validate the role of PARP inhibitors in mHSPC patients.
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- Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.N Engl J Med. 2017; 377: 338-351
- Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer.N Engl J Med. 2019; 381: 121-131
- Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer.N Engl J Med. 2019; 381: 13-24
- Integrative Clinical Genomics of Advanced Prostate Cancer.Cell. 2015; 162: 454
- Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer.N Engl J Med. 2022; 386: 1132-1142
- LBA5_PR - A phase III trial with a 2x2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: Overall survival with abiraterone acetate plus prednisone in PEACE-1.Annals of Oncology. 2021; 162: S1283-S1346
- Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.N Engl J Med. 2015; 373: 737-746
- Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer.N Engl J Med. 2017; 377: 352-360
- ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer.J Clin Oncol. 2019; 37: 2974-2986
- Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer.N Engl J Med. 2020; 383: 2345-2357
- Olaparib for Metastatic Castration-Resistant Prostate Cancer.N Engl J Med. 2020; 382: 2091-2102
- Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a.J Clin Oncol. 2020; 38: 3763-3772
- Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer.J Clin Oncol. 2013; 31: 1748-1757
- Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer.Eur Urol. 2017; 72: 34-42
- Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer.Cancer Discov. 2018; 8: 444-457
- PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer.J Clin Oncol. 2019; 37: 490-503
- Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide.Eur Urol. 2018; 74: 218-225
- Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3.J Clin Oncol. 2016; 34: 1402-1418
- Seven-Month Prostate-Specific Antigen Is Prognostic in Metastatic Hormone-Sensitive Prostate Cancer Treated With Androgen Deprivation With or Without Docetaxel.J Clin Oncol. 2018; 36: 376-382
- The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018; 50: 645-651
- Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.N Engl J Med. 2016; 375: 443-453
- DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.N Engl J Med. 2015; 373: 1697-1708
- Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial.Lancet Oncol. 2020; 21: 162-174
- Pre-specified interim analysis of GALAHAD: A phase 2 study of niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD).Annals of Oncology. 2019; 30
- Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations.Journal of Clinical Oncology. 2022; 40: 12
- PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).Journal of Clinical Oncology. 2022; 40: 11
- PARP Inhibitors for Advanced Prostate Cancer: Validating Predictive Biomarkers.Eur Urol. 2019; 76: 459-460
Published online: June 29, 2022
Accepted: June 21, 2022
Received in revised form: June 19, 2022
Received: May 7, 2022
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