Up to 30% of patients with metastatic castration-resistant prostate cancer have deleterious mutations in genes involved in homologous recombination repair of DNA damage. The use of the PARP inhibitor ...olaparib in such patients was associated with longer progression-free survival and a longer time to pain progression than control therapy.
Summary Background Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus ...prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment. Methods We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m2 mitoxantrone intravenously over 15–30 min or 25 mg/m2 cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov , NCT00417079. Findings 755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15·1 months (95% CI 14·1–16·3) in the cabazitaxel group and 12·7 months (11·6–13·7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95% CI 0·59–0·83, p<0·0001). Median progression-free survival was 2·8 months (95% CI 2·4–3·0) in the cabazitaxel group and 1·4 months (1·4–1·7) in the mitoxantrone group (HR 0·74, 0·64–0·86, p<0·0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 82% patients vs mitoxantrone, 215 58%) and diarrhoea (23 6% vs one <1%). 28 (8%) patients in the cabazitaxel group and five (1%) in the mitoxantrone group had febrile neutropenia. Interpretation Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy. Funding Sanofi-Aventis.
Abstract Prostate cancer is the most common cause of cancer in men, with 137.9 new cases per 100,000 men per year. The overall 5-year survival rate for prostate cancer is very high. Up to 20% of men ...who undergo state-of-the art treatment for prostate cancer will develop castration-resistant prostate cancer (CRPC) within 5 years, with median survival for those with metastatic CRPC ranging from approximately 15 to 36 months in recent studies. With the advent of several new drugs in the past 5 years to treat CRPC, the challenge facing clinicians is how to best sequence or combine therapies or both to optimize outcomes. A better understanding of the disease process and the role of the androgen receptor as a target for both therapy and resistance have led to the consideration of biomarkers as an approach to aid in selecting the appropriate agent for a given patient as patients respond to or tolerate different drugs differently. Research to identify new prognostic biomarkers, which are associated with outcome measures, as well as predictive biomarkers, which predict response or resistance to therapy is ongoing. The treatment of advanced prostate cancer and the research related to biomarkers are discussed.
Background
Biallelic loss‐of‐function BLM mutations result in Bloom syndrome: a genetic disorder characterized by growth deficiencies, photosensitivity, and multiple cancer susceptibilities. There ...are conflicting reports about whether or not heterozygous BLM carriers are at a higher risk of various cancers. Without BLM protein functionality, there is evidence of increased sister chromatid exchange and chromosomal instability.
Methods
Metastatic prostate cancer patients (N = 796) underwent germline genetic testing as part of routine care at three academic centers. Patients with heterozygous BLM mutations were identified. Tumor tissue was analyzed for somatic alterations in those patients who had a germline pathogenic mutation. Control data using a population sample were extracted from the Genome Aggregation Database.
Results
Heterozygous BLM germline mutations in 5 of 796 patients (prevalence, 0.63%). All mutations were loss‐of‐function truncating alterations. None of the mutations were BLMAsh. The control population (gnomAD) frequency of pathogenic or likely pathogenic BLM mutations was 0.18% (212 of 116 653). The relative risk (RR) of BLM mutations in metastatic prostate cancer patients was 3.4 (95% CI, 1.42‐8.33; P < .0062) compared to gnomAD controls. Tumor DNA sequencing in the BLM carriers showed no evidence of somatic BLM mutations. Interestingly, 3 of 5 BLM germline carriers had bi‐allelic BRCA2 inactivation evident on tumor sequencing. One patient had both germline and somatic mutations in BRCA2. Excluding the patient with the germline BRCA2 mutation (BLM prevalence, 4 of 796: 0.50%) still yielded a statistically significant finding vs the gnomAD controls (RR, 2.8; 95% CI, 1.02‐7.39; P < .04).
Conclusion
Truncating BLM germline mutations occur at a higher frequency in patients with advanced prostate cancer as compared to control populations. Though no biallelic loss of BLM was no noted in cancers, a surprising number of the BLM germline heterozygotes had pathogenic BRCA2 mutations in their tumor.
Prostate cancer is the third leading cause of cancer-related death in men in the United States. Although serious, most of these diagnoses are not terminal. Inherited risk for prostate cancer is ...associated with aggressive disease and poorer outcomes, indicating a critical need for increased genetic screening to identify disease-causing variants that can pinpoint individuals at increased risk for metastatic castration-resistant prostate cancer.
To identify positive (pathogenic, likely pathogenic, and increased risk) germline variants in a large prostate cancer cohort and to evaluate the usefulness of current practice guidelines in recognizing individuals at increased risk for prostate cancer who would benefit from diagnostic genetic testing.
Cross-sectional study of data from 3607 men with a personal history of prostate cancer who underwent germline genetic testing between 2013 and 2018 and were unselected for family history, stage of disease, or age at diagnosis. Referral-based testing was performed at a Clinical Laboratory Improvement Amendments/College of American Pathologists-certified diagnostic laboratory. All analysis took place between February 2017 and August 2018.
The frequency and distribution of positive germline variants, and the percentage of individuals with prostate cancer who met National Comprehensive Cancer Network (NCCN) guidelines for germline genetic testing.
Of 3607 men (mean SD age at testing, 67 9.51 years; mean age at diagnosis, 60 9.05 years) with a personal diagnosis of prostate cancer who were referred for genetic testing, 620 (17.2%) had positive germline variants, of which only 30.7% were variants in BRCA1/2. Positive variants in HOXB13, a gene associated only with prostate cancer risk, were identified in 30 patients (4.5%). DNA mismatch repair variants with substantial known therapeutic implications were detected in 1.74% of variants in the total population tested. Examination of self-reported family histories indicated that 229 individuals (37%) with positive variants in this cohort would not have been approved for genetic testing using the NCCN genetic/familial breast and ovarian guidelines for patients with prostate cancer.
Current NCCN guidelines and Gleason scores cannot reliably stratify patients with prostate cancer for the presence or absence of pathogenic germline variants. Most positive genetic test results identified in this study have important management implications for patients and their families, which underscores the need to revisit current guidelines.
Summary Background Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well ...tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. Methods In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov , number NCT00699751. Findings Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio HR 0·70, 95% CI 0·56–0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52–0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3–4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3–4 thrombocytopenia with radium-223 than with placebo (31 9% of 347 patients vs five 3% of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven 3% of 253 patients vs one 1% of 130 patients). The incidences of grade 3–4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. Interpretation Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. Funding Algeta ASA and Bayer HealthCare Pharmaceuticals.
Prostate specific membrane antigen (PSMA) represents a validated target for prostate cancer therapeutics. The phase III VISION study with
lutetium (
Lu)-PSMA-617 represented a pivotal step forward ...and the FDA has now approved this agent in advanced metastatic castrate-resistant prostate cancer (mCRPC). A number of other PSMA targeted radiopharmaceuticals are now under development. Some of these agents are targeted to PSMA via monoclonal antibodies such as J591 and TLX591. Others are targeted to PSMA via small molecules such as PSMA-617, PSMA I&T, MIP-1095, etc. In addition to the use of various ligands, multiple isotopes are now in clinical trials. Beta emitters in development include
Lu,
iodide (
I), and
copper (
Cu). Targeted alpha emitters potentially include
actinium (
Ac),
thorium (
Th), and
lead (
Pb). Phase III trials are underway with both
Lu-PSMA-617 and
Lu-PSMA I&T in mCRPC. Single dose phase I trials are complete with
Ac-J591 but additional data are need to launch a phase III. Data are promising with
Ac-PSMA-617 but concerns remain over salivary and renal toxicity. Tandem therapies are also considered combining both beta and alpha-targeted therapy. Taken together the field of PSMA targeted radiopharmaceuticals is rapidly developing. The targeted alpha therapies are particularly promising and several developmental paths forward are being considered in the near future.
Background
The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel‐T immunotherapy for ...asymptomatic/minimally symptomatic metastatic castration‐resistant prostate cancer (mCRPC).
Methods
PROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel‐T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow‐up was for ≥3 years or until death or study withdrawal.
Results
In 2011‐2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate‐specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel‐T infusions. The median OS was 30.7 months (95% confidence interval CI, 28.6‐32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4‐46.2 months). The incidence of sipuleucel‐T–related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person‐years was 1.2 (95% CI, 0.9‐1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results–Medicare database was 2.8%; the rate per 100 person‐years was 1.5 (95% CI, 1.4‐1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel‐T; 32.5% and 17.4% of the patients experienced 1‐ and 2‐year treatment‐free intervals, respectively.
Conclusions
PROCEED provides contemporary survival data for sipuleucel‐T–treated men in a real‐world setting of new life‐prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel‐T. The safety and tolerability of sipuleucel‐T in PROCEED were consistent with previous findings.
Sipuleucel‐T is an established cellular immunotherapy for treating metastatic castration‐resistant prostate cancer. The postapproval prospective registry trial PROCEED provides data on contemporary survival for sipuleucel‐T–treated men in an era of new life‐prolonging agents as well as the safety and tolerability of this immunotherapy in a real‐world setting.
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