Prostate cancer is an androgen-receptor–dependent disease, and the blocking of androgen-receptor signaling is a hallmark of prostate-cancer therapeutics. Although most patients initially benefit from ...therapy involving deprivation of gonadal androgen, the disease eventually progresses after 12 to 48 months, depending on the disease burden, host factors, and inherent tumor biology. After progression, the disease evolves into a new clinically and molecularly heterogeneous state known as castration-resistant prostate cancer, which is invariably fatal.
The clinical course of metastatic castration-resistant prostate cancer has changed considerably, primarily because of factors such as earlier diagnosis, stage migration, and changes in practice patterns. Earlier initiation . . .
Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, are being explored as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) in men harboring mutations in ...homologous recombination DNA-repair genes. Whether responses to PARP inhibitors differ according to the affected gene is currently unknown.
To determine whether responses to PARP inhibitors differ between men with BRCA1/2 and those with ATM mutations.
This was a multicenter retrospective review of 23 consecutive men with mCRPC and pathogenic germline and/or somatic BRCA1/2 or ATM mutations treated with olaparib at three academic sites in the USA.
The proportion of patients achieving a ≥50% decline in prostate-specific antigen (PSA50 response) was compared using Fisher's exact test. Clinical and radiographic progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier analyses and compared using the log-rank test.
The study included two men with BRCA1 mutations, 15 with BRCA2 mutations, and six with ATM mutations. PSA50 responses to olaparib were achieved in 76% (13/17) of men with BRCA1/2 versus 0% (0/6) of men with ATM mutations (Fisher's exact test; p=0.002). Patients with BRCA1/2 mutations had median PFS of 12.3mo versus 2.4mo for those with ATM mutations (hazard ratio 0.17, 95% confidence interval 0.05–0.57; p=0.004). Limitations include the retrospective design and relatively small sample size.
Men with mCRPC harboring ATM mutations experienced inferior outcomes to PARP inhibitor therapy compared to those harboring BRCA1/2 mutations. Alternative therapies should be explored for patients with ATM mutations.
Mutations in BRCA1/2 and ATM genes are common in metastatic prostate cancer. In this study we compared outcomes for men with BRCA1/2 mutations to those for men with ATM mutations being treated with olaparib. We found that men with ATM mutations do not respond as well as men with BRCA1/2 mutations.
In this retrospective review of 23 patients with BRCA1/2 or ATM mutations treated with olaparib, we found that none of six men with ATM mutations achieved a 50% decline in prostate-specific antigen, compared to 13/17 men with BRCA1/2 mutations. Patients with BRCA1/2 mutations also had longer progression-free survival on olaparib treatment. Men with metastatic castration-resistant prostate cancer harboring ATM mutations may not respond to PARP inhibitors as well as men with BRCA1/2 mutations and may require alternative therapies.
Introduction
Piflufolastat F‐18 (18F‐DCFPyL) prostate‐specific membrane antigen (PSMA) positron emission tomography (PET) imaging is approved by the US food and drug administration for initial ...staging of high‐risk prostate cancer, biochemical recurrence (BCR), and restaging of metastatic prostate cancer. Here, we sought to assess how its integration into clinical care may have impacted the management of patients.
Methods
We identified 235 consecutive patients who underwent an 18F‐DCFPyL PET scan from August 2021 to June 2022. The median prostate‐specific antigen at the time of imaging was 1.8 ng/mL (Range: 0−3740 ng/mL). Descriptive statistics were used to analyze its impact on clinical care for a subset of 157 patients with available treatment information: 22 for initial staging, 109 with BCR, and 26 patients with known metastatic disease.
Results
PSMA‐avid lesions were detected in 154/235 (65.5% of) patients. In patients undergoing initial staging, 18/39 (46.2% of) patients had extra‐prostatic metastatic lesions; 15/39 (38.5% of) scans were negative and 6/39 (15.4%) had equivocal results. 12/22 (54.5% of) patients had a change in their treatment plan post‐PSMA PET scan while 10/22 (45.5%) had no change in their treatment plan. In the BCR cohort, 93/150 (62.0%) had a local recurrence or metastatic lesions. Equivocal and negative scans accounted for 11/150 (7.3%) and 46/150 (30.7%) of scans, respectively. 37/109 (33.9% of) patients had a change in their treatment plan, while treatment was not altered in 72/109 (66.1% of) cases. In patients with metastatic disease, 43/46 (93.5%) had PSMA‐avid lesions identified; equivocal and negative scans accounted for 2/46 (4.3%) and 1/46 (2.2%) of scan results, respectively. 6/26 (23.1%) had their tentative treatment plan adjusted after the PSMA PET scan. No change in the treatment plan was observed in 20/26 (76.9% of) cases.
Conclusion
Integration of F‐18 PSMA PET imaging impacted clinical decision‐making and subsequent management across all stages of prostate cancer. It remains to be seen whether this translates into superior survival outcomes.
DNA repair gene mutations are present in 8-10% of localized prostate cancers. It is unknown whether this is influenced by clinicopathologic factors.
We interrogated localized prostate adenocarcinomas ...with tumor DNA sequencing information from the TCGA validated (n = 333) and Nature Genetics (n = 377) datasets. Homologous recombination repair genes included in our analysis were: ATM, BRCA1/2, CDK12, CHEK1/2, FANCA, FANCD2, FANCL, GEN1, NBN, PALB2, RAD51, and RAD51C. Proportions of cases with pathogenic DNA repair mutations (and in ATM/BRCA1/2 specifically) were reported by Gleason grade group, clinical T, pathologic T, and pathologic N stage. Odds ratios and Fisher's exact tests were used to compare proportions between categories.
Patients with Gleason grade groups 3 and higher were 2.2 times more likely to harbor any DNA repair mutation (95% CI: 1.2-4.2; 10.3% versus 5.0%) and were 2.7 times more likely to have BRCA1/2 or ATM mutations (95% CI: 1.3-6.6; 7.0% versus 2.7%) compared to those in Gleason grade groups 1-2. Patients with pathologic T3 and T4 stage (pT3/pT4) were 2.6 times more likely to have any DNA repair mutation (95% CI: 1.3-6.6; 13.0% versus 5.5%) and were 3.2 times more likely to have BRCA1/2 or ATM mutations (95% CI: 1.2-11.3; 9.5% versus 3.1%) compared to those with pT2 disease. There was no difference by clinical tumor or nodal stage. Among men with Gleason grade group ≥ 3 and clinical stage ≥ cT3, 21.3% (1 in 5) had a DNA repair mutation in any gene and 11.7% (1 in 9) had a mutation in ATM/BRCA1/2.
The prevalence of pathogenic DNA repair gene alterations is enriched in men with advanced tumor stages and higher Gleason grade groups, with maximal enrichment observed in those with Gleason grade group ≥ 3 and clinical stage ≥ cT3 disease. This information can be used to guide eligibility criteria for genomically targeted clinical trials in the neoadjuvant/adjuvant settings.
Recently, an entity known as salivary duct carcinoma with rhabdoid features (SDC-RF) has been associated with somatic
mutations. Here we present the first known case report of conventional SDC ...occurring in the setting of a germline
pathogenic variant accompanied by a somatic loss of heterozygosity at the
locus.
A 67-year-old man presented with chest and back pain and was found to have osteolytic lesions in the sternum and lumbar spine. Vertebral bone biopsies were positive for metastatic carcinoma of unknown primary. A molecular profiling assay consisting of both whole-exome next-generation sequencing (NGS) as well as immunohistochemistry (IHC) for select clinically-relevant proteins performed on the bone biopsy suggested a triple-negative (ER/PR/ERBB2 negative, by IHC), androgen receptor (AR IHC) positive tumor profile. Additionally, the assay uncovered a coding mutation in the
gene (c.1792C>T, p.R598*) with genomic loss of the second
allele. Germline testing returned positive for a heterozygous
pathogenic variant. PET-CT revealed a tumor in the neck suggestive of the primary malignancy consistent with that of salivary gland origin. The patient was initially treated with carboplatin and paclitaxel, then pembrolizumab, and finally with AR-directed therapy using leuprolide and enzalutamide. These treatments were not successful, and the patient eventually succumbed to his disease.
Molecular testing revealed that our patient had bi-allelic inactivation of the
gene. We believe our patient developed a somatic mutation in addition to his preexisting germline
mutation that ultimately predisposed him to SDC. While previous studies have found somatic
pathogenic variants in SDC-RF, our patient was found to have a germline
pathogenic variant in the setting of conventional SDC, without rhabdoid features. This case provokes questions regarding tumor genetics and molecular profiling of SDC in patients with germline
pathogenic variants. Moreover, this case supports the notion that SDC may be the salivary counterpart of other malignancies associated with germline
pathogenic variants and may possibly expand the spectrum of tumors that arise in this familial cancer-predisposition syndrome.
The notion that androgens and androgen receptor (AR) signaling are the hallmarks of prostate cancer oncogenesis and disease progression is generally well accepted. What is more poorly understood is ...the role of AR signaling in other human malignancies. This special issue of
initially reviews the role of AR in advanced prostate cancer, and then explores the potential importance of AR signaling in other epithelial malignancies. The first few articles focus on the use of novel AR-targeting therapies in castration-resistant prostate cancer and the mechanisms of resistance to novel antiandrogens, and they also outline the interaction between AR and other cellular pathways, including PI3 kinase signaling, transcriptional regulation, angiogenesis, stromal factors, Wnt signaling, and epigenetic regulation in prostate cancer. The next several articles review the possible role of androgens and AR signaling in breast cancer, bladder cancer, salivary gland cancer, and hepatocellular carcinoma, as well as the potential treatment implications of using antiandrogen therapies in these non-prostatic malignancies.
B7 homolog 3 (B7-H3; CD276), a tumor-associated antigen and possible immune checkpoint, is highly expressed in prostate cancer (PCa) and is associated with early recurrence and metastasis. ...Enoblituzumab is a humanized, Fc-engineered, B7-H3-targeting antibody that mediates antibody-dependent cellular cytotoxicity. In this phase 2, biomarker-rich neoadjuvant trial, 32 biological males with operable intermediate to high-risk localized PCa were enrolled to evaluate the safety, anti-tumor activity and immunogenicity of enoblituzumab when given before prostatectomy. The coprimary outcomes were safety and undetectable prostate-specific antigen (PSA) level (PSA
) 1 year postprostatectomy, and the aim was to obtain an estimate of PSA
with reasonable precision. The primary safety endpoint was met with no notable unexpected surgical or medical complications, or surgical delay. Overall, 12% of patients experienced grade 3 adverse events and no grade 4 events occurred. The coprimary endpoint of the PSA
rate 1 year postprostatectomy was 66% (95% confidence interval 47-81%). The use of B7-H3-targeted immunotherapy in PCa is feasible and generally safe and preliminary data suggest potential clinical activity. The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180.
Background
Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define ...pathological and clinical characteristics associated with germline DNA‐repair gene mutations, to facilitate selection of patients for germline testing.
Methods
We retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical‐grade assay (Color Genomics). This platform utilizes next‐generation sequencing from saliva to interrogate 30 cancer‐susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA‐sequence alterations (pathogenic or variants) were offered genetic counseling.
Results
Between July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation‐positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines.
Conclusions
Presence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA‐repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening.
Most men initially respond favourably to gonadal suppression, but virtually all eventually develop biochemical or clinical evidence of disease progression after around 2-10 years in the ...non-metastatic setting and 1-3 years in the metastatic setting.1 This clinical state, known as castration-resistant prostate cancer, is usually heralded by a shift in androgen signalling from gonadal androgens to adrenal and intratumoral androgens.
Recently there has been an explosion of new agents being investigated for the treatment of prostate cancer. These modalities represent new therapies aimed at old targets, and new therapies addressing ...new targets. This review will highlight three novel and emerging areas of treatment that have the potential to significantly impact the management of metastatic castration-resistant prostate cancer (mCRPC) in the near future: immunotherapy, poly ADP-ribose polymerase (PARP) inhibitors, and prostate-specific membrane antigen (PSMA)-targeted modalities. Immunotherapy, particularly immune checkpoint blockers, PARP inhibitors, and PSMA-targeted therapies are all increasingly being studied for the treatment of mCRPC although none are currently FDA-approved specifically for prostate cancer. Together these three classes of treatments may drastically change the future landscape of mCRPC. This review will cover what is currently known about the utility of these agents for the treatment of mCRPC, the areas of active research, and how these agents may be useful for patients in the future. It will also emphasize the notion of biomarker selection to help inform which patients are more likely to respond to these therapies.
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