Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood.
To investigate the ...clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations.
We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide.
We assessed the impact of germline DNA-repair gene mutation status on ≥50% and ≥90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses.
Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio HR 0.47; p=0.061), PFS (HR 0.50; p=0.090), and OS (HR 0.28; p=0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval CI 0.25–0.92; p=0.027), PFS (HR 0.52, 95% CI 0.28–0.98; p=0.044), and OS (HR 0.34, 95% CI 0.12–0.99; p=0.048), but not in men with non-BRCA/ATM germline mutations (all p>0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n=9) with BRCA/ATM mutations.
Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations.
Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide.
To determine whether and how germline DNA-repair gene mutations influence clinical outcomes to abiraterone or enzalutamide in patients with castration-resistant prostate cancer (CRPC), we performed germline genotyping for 50 DNA-repair genes using blood samples from 172 patients with CRPC beginning first-line systemic therapy with abiraterone or enzalutamide. We discovered that the presence of germline DNA-repair gene defects (particularly mutations in the BRCA1/2 and ATM genes) were associated with better outcomes to abiraterone and enzalutamide.
Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) ...and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline ≥ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.
Pharmacological inhibition of immune checkpoint receptors or their ligands represents a transformative breakthrough in the management of multiple cancers. However, immune checkpoint inhibitors have ...yet to be FDA-approved for the management of metastatic prostate cancer (PCa), the commonest non-cutaneous malignancy in men. Areas covered: We review our current understanding of the PD-1/PD-L1 pathway in cancer, the use of anti-PD-1/PD-L1 therapeutics in PCa, and potential subgroups of PCa patients who may derive the greatest benefit from these agents (such as men with tumors that have expression of PD-L1 and/or high mutational load). We also review the prior and current clinical trials evaluating the blockade of PD-1/PD-L1 in PCa, highlighting some of the key ongoing studies of greatest relevance to the field. Expert commentary: Clinical trials investigating PD-1/PD-L1 inhibitors should be encouraged in patients with PCa. While it is unlikely that immune checkpoint monotherapies will produce long-lasting responses in a substantial proportion of patients, there is early evidence of activity in some patient subsets. These subgroups may include those with high PD-L1 expression, those with hypermutated or microsatellite-unstable tumors, and those enriched for germline and/or somatic DNA-repair gene mutations (e.g. intraductal/ductal histology, primary Gleason pattern 5, and perhaps AR-V7-positive tumors).
Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current ...definitions of oligometastasis are solely numerical.
To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.
This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.
We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).
The frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio IRR 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio HR 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined.
Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration.
Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.
The frequency of putative driver mutations increases across the metastatic hormone-sensitive prostate cancer spectrum and can stratify clinical outcomes. Somatic mutational profiles help in redefining oligometastasis beyond simple lesion enumeration by providing a biological definition.
The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies ...established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7–driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors.
Despite the recent approval and widespread use of abiraterone acetate and enzalutamide for the treatment of castration‐resistant prostate cancer (CRPC), this disease still poses significant ...management challenges because of various tumor escape mechanisms, including those that allow androgen receptor (AR) signaling to remain active. These AR‐related resistance mechanisms include AR gene amplification or overexpression, constitutively active ligand‐independent AR splice variants, and gain‐of‐function mutations involving the AR ligand‐binding domain (LBD), among others. Therefore, the development of AR‐targeted therapies that function independently of the LBD represents an unmet medical need and has the potential to overcome many of these resistance mechanisms. This article discusses N‐terminal domain (NTD) inhibition as a novel concept in the field of AR‐directed therapies for prostate cancer. AR NTD‐targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR‐mediated transcriptional activity, and as a result, may affect a broader AR population including mutational and splice variant ARs. Indeed, the first clinical trial of an AR NTD inhibitor is now underway.
Implications for Practice:
Because of emerging resistance mechanisms that involve the ligand‐binding domain of the androgen receptor (AR), there is currently no effective treatment addressing tumor escape mechanisms related to current AR‐targeted therapies. Many patients still demonstrate limited clinical response to current hormonal agents, and castration‐resistant prostate cancer remains a lethal disease. Intense research efforts are under way to develop therapies to target resistance mechanisms, including those directed at other parts of the AR molecule. A novel small‐molecule agent, EPI‐506, represents a new pharmaceutical class, AR N‐terminal domain inhibitors, and shows preclinical promise to overcome many known resistance mechanisms related to novel hormonal therapies.
This article discusses N‐terminal domain (NTD) inhibition as a novel concept in the field of androgen receptor (AR)‐directed therapies for prostate cancer. AR NTD‐targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR‐mediated transcriptional activity and, as a result, may affect a broader AR population, including mutational and splice variant ARs.
The development of conditionally replicative adenoviruses (CRAds) for castration-resistant prostate cancer (CRPC), particularly neuroendocrine prostate cancer (NEPC), has two major obstacles: choice ...of control element and poor infectivity. We applied fiber-modification-based infectivity enhancement and an androgen-independent promoter (cyclooxynegase-2, COX-2) to overcome these issues.
The properties of the COX-2 promoter and the effect of fiber modification were tested in two CRPC cell lines (Du-145 and PC3). Fiber-modified COX-2 CRAds were tested in vitro for cytocidal effect as well as in vivo for antitumor effect with subcutaneous CRPC xenografts.
In both CRPC cell lines, the COX-2 promoter showed high activity, and Ad5/Ad3 fiber modification significantly enhanced adenoviral infectivity. COX-2 CRAds showed a potent cytocidal effect in CRPC cells with remarkable augmentation by fiber modification. In vivo, COX-2 CRAds showed an antitumor effect in Du-145 while only Ad5/Ad3 CRAd showed the strongest antitumor effect in PC3.
COX-2 promoter-based, infectivity-enhanced CRAds showed a potent antitumor effect in CRPC/NEPC cells.
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