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Background Biomarkers predicting second-generation novel hormonal therapy (NHT) benefit relative to taxanes are critical for optimized treatment decisions for metastatic castration-resistant prostate cancer (mCRPC) patients. These associations have not been reported simultaneously for common mCRPC genomic biomarkers. Objective To evaluate predictive associations of common genomic aberrations in mCRPC using an established comprehensive genomic profiling (CGP) system. Design, setting, and participants A retrospective cohort study used data from a deidentified US-based clinicogenomic database comprising patients treated in routine clinical practice between 2011 and 2020, evaluated with Foundation Medicine CGP in tissue biopsies obtained around the time of treatment decision. The main cohort included 180 NHT and 179 taxane lines of therapy (LOTs) from 308 unique patients. The sequential cohort comprised a subset of the main cohort NHT LOTs immediately followed by taxane from 55 unique patients. Outcome measurements and statistical analysis Prostate-specific antigen (PSA) response, time to next treatment (TTNT), and overall survival (OS) were assessed. Main cohort analyses were adjusted for known treatment assignment biases via inverse probability of treatment weighting (IPTW) in treatment interaction models. Results and limitations In the main cohort, patients with AR amplification (ARamp) or PTEN aberrations (PTENalt) had worse relative PSA response on NHT versus taxanes compared with patients without. Patients with ARamp, PTENalt, or RB1 aberrations (RB1alt) also had worse relative TTNT and OS on NHT but not on taxanes. In multivariable models for TTNT and OS adjusted via IPTW, ARamp, PTENalt, and RB1alt were shown as poor prognostic factors overall and demonstrated significant treatment interactions, indicating reduced hazards of therapy switch and death on taxanes versus NHT. Consistent associations favoring increased benefit from subsequent taxane despite prior NHT treatment line were observed only for ARamp in the sequential cohort, in which very few patients had RB1alt for assessment. Conclusions ARamp status is a candidate biomarker to predict poor effectiveness of NHT relative to taxanes in mCRPC in scenarios where both options are considered. Patient summary Specific alterations in the DNA of tumors may assist in choosing between novel oral hormonal therapies and standard chemotherapy in advanced prostate cancer patients.

Mechanisms that protect DNA are crucial to preserve the genome integrity from injuries produced by environmental agents or those spontaneously generated during DNA metabolism.1 DNA single-strand breaks (SSBs) are repaired by mismatch repair (MMR), base excision repair (BER) and nucleotide excision repair (NER).1 Non-homologous end joining (NHEJ) or homologous recombination repair (HRR) processes double-strand breaks (DSBs).1 While NHEJ solves DSBs in a potentially inaccurate way, HRR is an error-free pathway that restores the genomic sequence of the broken DNA ends by using the sister chromatid as template for repair.1 Several proteins are involved in the HRR pathway: some of them act as sensors of DSBs such as γH2AX, ATM and ATR, leading to the activation of signal mediator proteins (ie, BRCA1, BRCA2 and PALB2). The final event of the HRR pathway is the loading of a small nuclear protein called RAD51 onto single-stranded DNA, where it promotes strand invasion and replication fork stabilisation (figure 1).2 Tumours with HRR deficiency (HRD) were described for the first time in cancers that harbour germline mutations of the tumour suppressors BRCA1 and BRCA2 (BRCA1/2 ).3 Nonetheless, genetic and epigenetic events can also result in inactivation of other HRR components, leading to HRD in sporadic cancers.3 Figure 1 Homologous recombination pathway. Adapted from De Picciotto et al. 50 HRD is harboured by approximately 13% and 15% of ovarian and triple negative breast cancers (TNBC), respectively, and it is attributable to germline BRCA1/2 ( gBRCA1/2 ) mutations.4 5 Furthermore, 50% and 40% of ovarian and TNBC, respectively, are characterised by harbouring HRD in the absence of gBRCA1/2 mutations.4 6 Also, 10%–12% of advanced prostate cancer harbour germline or somatic BRCA2 inactivation and up to 25% contain a DNA repair defect.7 As HRR is required for the repair of DSBs …

BACKGROUND Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. OBJECTIVE To determine whether gDDRm status impacts benefit from established therapies in mPC. DESIGN, SETTING, AND PARTICIPANTS This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used. RESULTS AND LIMITATIONS The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm+], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm-]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2 vs 3.0 yr, p=0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm- (5.1 mo), and RRs were similar (gDDRm+=61%; gDDRm-=54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+=8.3 mo, gDDRm-=8.3 mo; gDDRm+=46%, gDDRm-=56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28-1.25; p=0.17). Results are limited by the retrospective nature of the analysis. CONCLUSIONS mPC patients with gDDRm appeared to benefit from standard therapies similarly to the overall population; prospective studies are ongoing to investigate the impact of PARPi/platinum. PATIENT SUMMARY Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients.