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The PROfound trial evaluated the PARP inhibitor olaparib in metastatic castration-resistant prostate cancers harboring alterations in BRCA1/2 and ATM (cohort A) and in 12 other homologous recombination repair genes (cohort B). Olaparib led to more objective responses and longer radiographic progression-free survival than the control in cohort A and when cohorts A and B were combined. The efficacy of olaparib in cohort B was a secondary objective prespecified in the trial protocol but was not reported. Reconstructing patient-level data for cohort B, two of 54 patients (4%) in the olaparib arm and two of 24 patients (8%) in the control arm had a radiographic response, and there was no evidence that olaparib prolonged radiographic progression-free survival in cohort B (hazard ratio 0.88, 95% confidence interval 0.58-1.34). These results are in strong contrast to cohort A. PATIENT SUMMARY: A large clinical study concluded that treatment with the PARP inhibitor olaparib benefits men with metastatic castration-resistant prostate cancer whose tumors harbor alterations in 15 different DNA repair genes. In contrast to the group dominated by BRCA alterations, any potential benefit from olaparib was considerably less, if present at all, for men with prostate cancers harboring one of the 12 other, non-BRCA DNA repair alterations.

Background CDK12 genomic alterations occur in several tumor types, but little is known about their oncogenic role and clinical significance. Objective To describe the landscape of CDK12 alterations across solid cancers and the clinical features of CDK12-altered prostate cancer. Design, setting, and participants A single-center retrospective study of 26743 patients across 25 solid tumor types who underwent tumor sequencing was performed. Clinicopathologic features and outcomes were assessed in prostate cancer. Outcome measurements and statistical analysis CDK12 alterations and their association with genomic characteristics are described. For prostate cancer patients, overall survival and time to castration resistance were assessed using univariable and multivariable Cox regression analysis. Results and limitations CDK12 alterations were identified in 404/26743 patients (1.5%) overall, but were most frequent in prostate (100/1875, 5.3%) and ovarian cancer (43/1034, 4.2%), in which they were associated with a high prevalence of truncating variants and biallelic inactivation. CDK12 alterations defined a genomic subtype of prostate cancer with a unique copy-number alteration profile and involvement of distinct oncogenic pathway alterations, including cell-cycle pathway genes. CDK12-altered prostate cancer was associated with somewhat more aggressive clinical features and shorter overall survival (median 64.4 vs 74.9 mo; p = 0.032) independent of standard clinical factors and tumor copy-number alteration burden (adjusted hazard ratio 1.80, 95% confidence interval 1.12–2.89; p = 0.024). The study is limited by its retrospective nature. Conclusions CDK12 alteration is a rare event across solid cancers but defines a clinically distinct molecular subtype of prostate cancer associated with unique genomic alterations and slightly more aggressive clinical features. Patient summary CDK12 gene alterations occur rarely across tumor types, but more frequently in prostate cancer, where they are associated with genomic instability, cell-cycle pathway gene alterations, and somewhat worse clinical outcomes, warranting further investigation of therapeutic targeting of this disease subset.

BRCA2 alterations predict for a response to poly-ADP-ribose polymerase inhibition in metastatic castration-resistant prostate cancer (mCRPC). However, detection is hindered by insufficient tumor tissue and low sensitivity of cell-free DNA for detecting copy number loss.To evaluate the BRCA2 loss detection using single-cell, shallow whole-genome sequencing (sWGS) of circulating tumor cells (CTCs) in patients with mCRPC.We analyzed CTC samples collected concurrently with tumor biopsies intended for clinical sequencing in patients with progressing mCRPC.Differences in proportions were evaluated using the chi-square test. Correlations between assays were analyzed in linear regression models. Associations between alterations and genomic instability were assessed on the single-cell level using mixed-effect negative binomial models.We identified 138 patients with concurrent CTC and biopsy samples. CTC sWGS generated copy number profiles in a similar proportion of patients to biopsy samples (83% vs 78%, p = 0.23), but was more effective than bone biopsies (79% vs 50%; p = 0.009). CTC sWGS detected BRCA2 loss in more patients than tissue at the ≥1 (42% vs 16%; p0.001) and ≥2 (27% vs 16%; p = 0.028) CTC thresholds. The overall prevalence of BRCA2 loss was not increased in CTCs using sample-level composite z scores (p = 0.4), but was significantly increased compared with a lower-than-expected prevalence in bone samples (21% vs 3%, p = 0.014). Positive/negative predictive values for CTC BRCA2 loss were 89%/96% using the ≥1 CTC threshold and 67%/92% using the composite z score. CTC BRCA2 loss was associated with higher genomic instability in univariate (1.4-fold large-scale transition difference, 95% confidence interval [CI]: 1.2-1.6; p0.001) and multivariable analysis (1.4-fold difference, 95% CI: 1.2-1.6; p0.001).Copy number profiles can reliably be generated using CTC sWGS, which detected a majority of tissue-confirmed BRCA2 loss and "CTC-only" losses. BRCA2 losses were supported by increases in genomic instability.Current testing strategies have limitations in their ability to detect BRCA2 loss, a relatively common alteration in prostate cancer that is used to identify patients who may benefit from targeted therapy. In this paper, we evaluated whether we could detect BRCA2 loss in individual tumor cells isolated from patient blood samples and found this method to be suitable for further analysis.

Not available, Research letter

Background Growing evidence shows that clinical and molecular subtypes of prostate cancer (PCa) have specific risk factors. Observational studies suggest that physical activity may lower the risk of aggressive PCa. To our knowledge, the association between physical activity and PCa defined by TMPRSS2:ERG has not been evaluated. Objective To prospectively examine the association between physical activity and risk of PCa defined by clinical features and TMPRSS2:ERG. Design, setting, and participants We studied 49 160 men aged 40–75 yr in the Health Professionals Follow-up Study from 1986 to 2012. Data was collected at baseline and every 2 yr with >90% follow-up. Total and vigorous physical activity were measured in metabolic equivalent of task (MET)-h/wk. Outcome measures and statistical analysis Advanced PCa was defined as stage T3b, T4, N1, or M1 at diagnosis and lethal PCa as distant metastases or death due to disease over follow-up. Presence of TMPRSS2:ERG was estimated by immunohistochemistry of ERG protein expression. Cox proportional hazards models were used to obtain multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence of subtype-specific PCa. Results and limitations During 26 yr of follow-up, 6411 developed PCa overall and 888 developed lethal disease. There were no significant associations between total physical activity and risk of PCa in the overall cohort. In multivariable-adjusted models, men in the highest quintile of vigorous activity had a significant 30% lower risk of advanced PCa (HR: 0.70, 95% CI: 0.53–0.92) and 25% lower risk of lethal PCa (HR: 0.75, 95% CI: 0.59–0.94) than men in the lowest quintile of vigorous activity. The association was independent of screening history. Vigorous activity was not associated with total PCa in the overall cohort but was inversely associated among highly screened men (top vs bottom quintile, HR: 0.83, 95% CI: 0.70–0.97). Of all cases, 945 were assayed for ERG (48% ERG-positive). Men with higher vigorous activity had a lower risk of ERG-positive PCa (top vs bottom quintile, HR: 0.71, 95% CI: 0.52–0.97). There was no significant association with the risk of ERG-negative disease (p heterogeneity = 0.09). Conclusions Our study confirms that vigorous physical activity is associated with lower risk of advanced and lethal PCa and provides novel evidence for a lower risk of TMPRSS2:ERG-positive disease. Patient summary The identification of modifiable lifestyle factors for prevention of clinically important prostate cancer (PCa) is needed. In this report, we compared risk of PCa in men with different levels of physical activity. Men with higher vigorous activity had a lower risk of developing advanced and lethal PCa and PCa with the common TMPRSS2:ERG gene fusion.