The Prognostic Significance of Homologous Recombination Repair Pathway Alterations in Metastatic Hormone Sensitive Prostate Cancer |
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| Affiliation: | 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;1. Department of Urology, Foundation IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy;2. Department of Urology, University of Trieste, Cattinara Hospital - ASUGI, Trieste, Italy;3. Department of Radiology, Foundation IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, University of Milan, Milan, Italy;4. Department of Radiology, University of Trieste, Cattinara Hospital, Trieste, Italy;1. Department of Urology, UT Southwestern Medical Center, Dallas, TX;2. UT Southwestern School of Medicine, Dallas, TX;3. Department of Urology, UC San Diego Medical Center, San Diego, CA;1. Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH;2. Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH;1. Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France;2. CEMKA, Bourg-la-Reine, France;3. Ipsen Pharma, Boulogne-Billancourt, France;4. University Hospital Jean Minjoz, Besançon, France;1. Albert Einstein College of Medicine, Bronx, NY;2. Department of Urology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY;3. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY;4. Division of Urology, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ;5. Cancer Institute of New Jersey, Newark, NJ;1. Dana-Farber Cancer Institute, Boston, MA;2. Seagen Inc., Bothell, WA;3. Astellas Pharma Global Development, Inc., Northbrook, IL;4. RTI- Health Solutions, Research Triangle Park, NC;5. EPI-Q Inc., Oakbrook, IL |
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| Abstract: | IntroductionThe 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.MethodsWe 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.Results151 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.ConclusionHRR 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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