The Prognostic Significance of Homologous Recombination Repair Pathway Alterations in Metastatic Hormone Sensitive Prostate Cancer

Aaron M Lee; Ava Saidian; Justin Shaya; Taylor Nonato; Angelo Cabal; J Michael Randall; Frederick Millard; Tyler Stewart; Brent Rose; Pablo Tamayo; Rana R McKay

doi:10.1016/j.clgc.2022.06.016

The Prognostic Significance of Homologous Recombination Repair Pathway Alterations in Metastatic Hormone Sensitive Prostate Cancer

Clin Genitourin Cancer. 2022 Dec;20(6):515-523. doi: 10.1016/j.clgc.2022.06.016. Epub 2022 Jun 30.

Authors

Affiliations

¹ Department of Medicine, Division of Hematology-Oncology, University of California San Diego, La Jolla, CA.
² Department of Urology, University of California San Diego, La Jolla, CA.
³ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA.
⁴ Department of Medicine, Division of Hematology-Oncology, University of California San Diego, La Jolla, CA; Department of Urology, University of California San Diego, La Jolla, CA; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA.
⁵ Department of Medicine, Division of Hematology-Oncology, University of California San Diego, La Jolla, CA. Electronic address: rmckay@health.ucsd.edu.

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: BRCA2; Biomarker; CDK12; CRPC; HRR; PARP inhibitors; PSA.

MeSH terms

Hormones
Humans
Male
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
Prognosis
Prospective Studies
Prostate-Specific Antigen
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / genetics
Prostatic Neoplasms, Castration-Resistant* / pathology
Recombinational DNA Repair / genetics
Retrospective Studies

Substances

Poly(ADP-ribose) Polymerase Inhibitors
Prostate-Specific Antigen
Hormones

Grants and funding

P30 CA023100/CA/NCI NIH HHS/United States