PMID- 38452035 OWN - NLM STAT- MEDLINE DCOM- 20240503 LR - 20240520 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 29 IP - 5 DP - 2024 May 3 TI - A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR). PG - 450-e725 LID - 10.1093/oncolo/oyae030 [doi] AB - BACKGROUND: Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. 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(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. METHODS: This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. RESULTS: The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade >/= 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. CONCLUSION: Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946). CI - (c) The Author(s) 2024. Published by Oxford University Press. FAU - Sahu, Kamal Kant AU - Sahu KK AUID- ORCID: 0000-0002-0382-6882 AD - Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. FAU - Li, Haoran AU - Li H AD - Division of Medical Oncology, Department of Internal Medicine, University of Kansas Cancer Center, Westwood, KS, USA. FAU - Mathew Thomas, Vinay AU - Mathew Thomas V AD - Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. FAU - Benson, Mallory AU - Benson M AD - Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. FAU - Boucher, Ken AU - Boucher K AD - Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. FAU - Gupta, Sumati AU - Gupta S AD - Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. FAU - Kohli, Manish AU - Kohli M AUID- ORCID: 0000-0002-9735-6614 AD - Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. FAU - Swami, Umang AU - Swami U AD - Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. FAU - Agarwal, Neeraj AU - Agarwal N AUID- ORCID: 0000-0003-1076-0428 AD - Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. FAU - Maughan, Benjamin L AU - Maughan BL AD - Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. LA - eng SI - ClinicalTrials.gov/NCT03533946 GR - 111833/University of Utah/ PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 8237F3U7EH (rucaparib) RN - 0 (Indoles) RN - 0 (Poly(ADP-ribose) Polymerase Inhibitors) RN - 0 (BRCA2 Protein) RN - 0 (BRCA2 protein, human) RN - 0 (BRCA1 Protein) RN - 0 (BRCA1 protein, human) SB - IM MH - Humans MH - Male MH - *Prostatic Neoplasms/genetics/drug therapy/pathology MH - Aged MH - *Indoles/therapeutic use MH - Middle Aged MH - *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/pharmacology MH - *Genotype MH - BRCA2 Protein/genetics MH - Aged, 80 and over MH - Germ-Line Mutation MH - BRCA1 Protein/genetics PMC - PMC11067793 OTO - NOTNLM OT - BRCAness OT - PARP OT - prostate cancer OT - rucaparib COIS- Sumati Gupta has received research funding from Mirati Therapeutics, Novartis, Pfizer, Viralytics, Hoosier Cancer Research Network, Rexahn Pharmaceuticals, Five Prime Therapeutics, Incyte, MedImmune, Merck, Bristol Myers Squibb, Clovis Oncology, LSK BioPharma, LSK/Elevar Therapeutics, QED Therapeutics, Debiopharm, Daiichi Sankyo/Lilly, Immunocore, Seattle Genetics, Astellas, Acrotech, and AstraZeneca; travel expenses from QED; and spouse owns stock in Salarius Pharmaceutical. Umang Swami reports consultancy to Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, Pfizer, AstraZeneca, and Gilead and research funding to institute from Janssen, Exelixis, and Astellas/Seattle Genetics. Neeraj Agarwal (lifetime disclosures): consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; research funding tos institution from Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Benjamin Maughan is a paid consultant/advisor to Abbvie, Pfizer, AVEO Oncology, Janssen, Astellas, Bristol-Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology, Lilly, Sanofi, Telix, and Peloton Therapeutics; Huntsman Cancer Institute has received research funding from Exelixis, Bavarian-Nordic, Clovis, Genentech, and Bristol-Myers Squibb on his behalf. The other authors indicated no financial relationships. EDAT- 2024/03/07 18:42 MHDA- 2024/05/03 12:53 PMCR- 2024/03/07 CRDT- 2024/03/07 13:54 PHST- 2023/10/17 00:00 [received] PHST- 2024/01/10 00:00 [accepted] PHST- 2024/05/03 12:53 [medline] PHST- 2024/03/07 18:42 [pubmed] PHST- 2024/03/07 13:54 [entrez] PHST- 2024/03/07 00:00 [pmc-release] AID - 7623988 [pii] AID - oyae030 [pii] AID - 10.1093/oncolo/oyae030 [doi] PST - ppublish SO - Oncologist. 2024 May 3;29(5):450-e725. doi: 10.1093/oncolo/oyae030.