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

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.

Lee AM ，Saidian A ，Shaya J ，Nonato T ，Cabal A ，Randall JM ，Millard F ，Stewart T ，Rose B ，Tamayo P ，McKay RR ... -  《-》

Co-occurring BRCA2/SPOP Mutations Predict Exceptional Poly (ADP-ribose) Polymerase Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer.

Orme JJ ，Taza F ，De Sarkar N ，Tewari AK ，Arsalan Naqvi S ，Riaz IB ，Childs DS ，Omar N ，Adra N ，Ashkar R ，Cheng HH ，Schweizer MT ，Sokolova AO ，Agarwal N ，Barata P ，Sartor O ，Bastos D ，Smaletz O ，Berchuck JE ，McClure H ，Taplin ME ，Aggarwal R ，Sternberg CN ，Vlachostergios PJ ，Alva AS ，Mehra N ，Nelson PS ，Hwang J ，Dehm SM ，Shi Q ，Fleischmann Z ，Sokol ES ，Elliott A ，Huang H ，Bryce A ，Marshall CH ，Antonarakis ES ... -  《European Urology Oncology》

The prevalence of gene mutations in homologous recombination repair pathways in Japanese patients with metastatic castration-resistant prostate cancer in real-world clinical practice: The multi-institutional observational ZENSHIN study.

Metastatic castration-resistant prostate cancer (mCRPC) is a genetically heterogeneous disease with a poor prognosis. The prevalence of mutations in homologous recombination repair (HRR) pathway genes, including BRCA1/2, as well as treatment patterns and clinical outcomes, are not well characterized among Japanese men with mCRPC. This multicenter, noninterventional cohort study enrolled Japanese men with mCRPC from 24 institutions between 2014 and 2018. Mutations in the 15 HRR-related genes were assessed using archival primary or metastatic tumor samples. Patterns of sequential therapies for mCRPC were investigated. Patients were followed up for survival evaluation including prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS). Of the 143 patients analyzed, HRR-related mutations were detected in 51 patients (35.7%). The most frequently mutated genes were CDK12 (N = 19, 13.3%), followed by BRCA2 (N = 18, 12.6%), ATM (N = 8, 5.6%), and CHEK2 (N = 3, 2.1%). The most common type of first-line therapy for mCRPC was next-generation hormonal agents (NHA, 44.4%), followed by first-generation antiandrogens (FGA, 30.3%), and taxanes (22.5%). Commonly prescribed first-/second-line sequential regimens included FGA/NHA (17.6%), NHA/NHA (15.5%), and NHA/taxanes (14.1%). The median PSA-PFS and OS for the entire cohort were 5.6 and 26.1 months, respectively. Patients carrying BRCA1/2 mutations had numerically shorter PSA-PFS (median 3.3 vs. 5.9 months) and OS (median 20.7 vs. 27.3 months) than those without mutations. In conclusion, approximately one-third of Japanese patients with mCRPC carried mutations in HRR-related genes in this study. The real-world outcomes of mCRPC are poor with conventional therapy, warranting an expansion of treatment options based on genetic abnormalities of the disease.

Uemura H ，Oya M ，Kamoto T ，Sugimoto M ，Shinozaki K ，Morita K ，Koto R ，Takahashi M ，Nii M ，Shin E ，Nonomura N ... -  《Cancer Medicine》

Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes.

Although germline BRCA mutations have been associated with adverse outcomes in prostate cancer (PC), understanding of the association between somatic/germline alterations in homologous recombination repair (HRR) genes and treatment outcomes in metastatic castration-resistant PC (mCRPC) is limited. The aim of this study was to investigate the prevalence and outcomes associated with somatic/germline HRR alterations, particularly BRCA1/2, in patients initiating first-line (1L) mCRPC treatment with androgen receptor signalling inhibitors (ARSi) or taxanes. Data from 729 mCRPC patients were pooled for CAPTURE from four multicentre observational studies. Eligibility required 1L treatment with ARSi or taxanes, adequate tumour samples and biomarker panel results. Patients underwent paired normal and tumour DNA analyses by next-generation sequencing using a custom gene panel including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B and RAD54L. Patients were divided into subgroups based on somatic/germline alteration(s): with BRCA1/2 mutations (BRCA); with HRR mutations except BRCA1/2 (HRR non-BRCA); and without HRR alterations (non-HRR). Patients without BRCA1/2 mutations were classified as non-BRCA. Radiographic progression-free survival (rPFS), progression-free survival 2 (PFS2) and overall survival (OS) were assessed. Of 729 patients, 96 (13.2%), 127 (17.4%) and 506 (69.4%) were in the BRCA, HRR non-BRCA and non-HRR subgroups, respectively. BRCA patients performed significantly worse for all outcomes than non-HRR or non-BRCA patients (P < 0.05), while PFS2 and OS were significantly shorter for BRCA than HRR non-BRCA patients (P < 0.05). HRR non-BRCA patients also had significantly worse rPFS, PFS2 and OS than non-HRR patients. Exploratory analyses suggested that for BRCA patients, there were no significant differences in outcomes associated with 1L treatment choice (ARSi or taxanes) or with the somatic/germline origin of the alterations. Worse outcomes were observed for mCRPC patients in the BRCA subgroup compared with non-BRCA subgroups, either HRR non-BRCA or non-HRR. Despite its heterogeneity, the HRR non-BRCA subgroup presented worse outcomes than the non-HRR subgroup. Screening early for HRR mutations, especially BRCA1/2, is crucial in improving mCRPC patient prognosis.

Olmos D ，Lorente D ，Alameda D ，Cattrini C ，Romero-Laorden N ，Lozano R ，Lopez-Casas PP ，Jambrina A ，Capone C ，Vanden Broecke AM ，Trevisan M ，Van Sanden S ，Jürgens A ，Herrera-Imbroda B ，Castro E ... -  《-》

DNA-Damage-Repair Gene Alterations in Genitourinary Malignancies.

High-fidelity repair of DNA damage repair (DDR) (either single-strand- [SSBs] or double-strand breaks [DSBs]) is necessary for maintaining genomic integrity and cell survival. DDR alterations are commonly found in genitourinary malignancies involving either DSB repair by the homologous recombination (HR) repair (HRR) system (BRCA1/2 pathway) or the SSB repair through the poly (ADP-ribose) polymerase (PARP) pathway. PARP inhibitors (PARPi) exploit defects in the DNA repair pathway through synthetic lethality, DSBs being repaired only in HR-proficient cells but not in HR-deficient (HRD) cells. A growing body of evidence supports the need for identification of germinal and somatic DDR alterations in patients with genitourinary malignancies. PARPi have already shown significant survival benefits in patients harboring HRR mutations in advanced settings, paving the way for precision medicine. In advanced prostate cancer (PCa), somatic mutations in HRR pathway are observed in up to 27% of metastatic resistant-to-castration PCa (mCRPC), although occurring early in PCa development, and mainly involving BRCA2, ATM, CHEK2, and BRCA1. Overall, germinal alterations are present in roughly 30-50% of cases of HRR alterations, and relative risk of PCa in germinal BRCA2 alteration carriers is 4.65-fold higher compared to noncarriers. Determination of DDR gene status is recommended in metastatic patients, a fortiori in mCRPC setting, since it could be a putative biomarker of response to first line of treatment (androgen-receptor signaling inhibitors [ARSI] vs. taxane-based chemotherapy) and allows to assess eligibility for PARPi use. Thus, olaparib (combined with androgen deprivation therapy) recently improved overall survival in mCRPC HRD patients, after new hormonal therapy (NHT) and led to its approvement for patients with an alteration in 14 of 15 prespecified HRR genes. Moreover, since preclinical data suggested synergic action between PARPi and ARSI, the use of either olaparib or niraparib has also been proposed in combination with NHT, with a radiological progression-free survival improvement when used with abiraterone. In urothelial carcinoma, a DDR gene alteration is identified in 23-54% of patients mostly in muscle-invasive bladder cancer, with a strong association between DDR gene mutation and a higher tumor mutation burden and sensitivity to cisplatin-based chemotherapy and immunotherapy. Recent phase 2 trials supported the use of HRR status to select patients for PARPi treatment in advanced urothelial carcinoma. Finally, in renal cell carcinomas (RCCs), pathogenic germline variants in DDR genes were identified in 7.3% of the cases, and deleterious somatic alterations have also been described as recurrent genomic events in patients with advanced RCC.

Dariane C ，Timsit MO 《-》