For decades, the management of patients with advanced prostate cancer has been hormonal therapy, known as androgen deprivation therapy, which is intended to lower testosterone levels. Further ...incremental progress in the treatment of men with metastatic hormone‐sensitive prostate cancer (mHSPC) has come from the addition of docetaxel or abiraterone acetate to androgen deprivation therapy for more aggressive upfront treatment regimens. Other combinatorial regimens testing the addition of novel therapies currently are in the late stages of development and are expected to further improve the clinical outcomes of these patients. The emergence of new positron emission tomography tracers specifically for prostate cancer, particularly prostate‐specific membrane antigen and fluciclovine, has increased the ability to detect metastatic disease earlier in the course of the disease and has helped to describe a new group of patients with mHSPC and oligometastatic disease. For this group of patients with mHSPC, the authors discuss the existing data with metastasis‐directed therapy and primary tumor‐directed therapy.
Progress in the treatment of men with metastatic hormone‐sensitive prostate cancer has come from the addition of docetaxel or abiraterone acetate to androgen deprivation therapy for more aggressive upfront treatment regimens. Other combinatorial regimens currently are in the late stages of development and are expected to further improve the clinical outcomes of these patients. The emergence of new positron emission tomography tracers has helped to diagnose metastatic hormone‐sensitive prostate cancer with oligometastases, for which the authors discuss the existing data with metastasis‐directed therapy and primary tumor‐directed 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.
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.
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.
Background
Prostate‐specific membrane antigen (PSMA) is a well‐established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody‐drug ...conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti‐PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA‐positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate‐specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration‐resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy.
Methods
A total of 119 (84 chemotherapy‐experienced and 35 chemotherapy‐naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events AEs, clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed.
Results
PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy‐naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy‐naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy‐naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy‐experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy‐naïve group had partial responses. The most common treatment‐related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis.
Conclusions
PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment‐related AEs included neutropenia and neuropathy.
Abstract Context We have recently witnessed a rapid increase in the number of effective systemic agents for men with metastatic castration-resistant prostate cancer (CRPC), including novel hormonal ...therapies (abiraterone acetate and MDV3100), immunotherapies (sipuleucel-T), chemotherapies (cabazitaxel), and bone microenvironment targeting agents (denosumab, radium 223). Given the increasing complexity of treatment decisions for this disease, major research and clinical priorities are (1) finding biomarkers that enable an understanding of the natural history and complex biology of this heterogeneous malignancy, (2) defining predictive biomarkers that identify men most likely to benefit from a given therapy, and (3) identifying biomarkers of early response or progression to optimize outcomes. Objective In this review, we discuss existing and potential biomarkers in CRPC and how they may currently inform prognosis, aid in treatment selection (predictive value), and relate to survival outcomes (surrogacy). Evidence acquisition PubMed-based literature searches and abstracts through September 2011 provided the basis for this literature review as well as expert opinion. Evidence synthesis We address blood and urine-based biomarkers such as prostate-specific antigen, lactate dehydrogenase, total and bone alkaline phosphatase and other bone turnover markers, hemoglobin, and circulating tumor cells in the context of prognosis, prediction, and patient selection for therapy. Given the inherent problems associated with defining progression-free survival in CRPC, the importance of biomarker development and the needed steps are highlighted. We place the discussion of biomarkers within the context of the design/intent of a trial and mechanism of action of a given systemic therapy. We discuss novel biomarker development and the pathway for surrogate or predictive biomarkers to become credentialed as useful tests that inform therapeutic decisions. Conclusions A greater understanding of biomarkers in CRPC permits a more personalized approach to care that maximizes benefit and minimizes harm and can inform clinical trials tailored to men most likely to derive benefit.
Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows ...resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on mCRPC, results from additional phase 3 studies with novel antiandrogens which are directed at inhibition of the AR (e.g., MDV3100), as well as other agents, are awaited with interest and may further expand the treatment choices for this difficult-to-manage population of patients.
Background
Retrospective analyses of randomized trials suggest that Black men with metastatic castration‐resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a ...prospective study of abiraterone acetate plus prednisone to explore outcomes by race.
Methods
This race‐stratified, multicenter study estimated radiographic progression‐free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate‐specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome‐wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self‐identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients.
Results
The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men.
Conclusions
Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side‐effect rates than White men. This exploratory genome‐wide analysis of TTP identified a possible candidate marker of ancestry‐dependent treatment outcomes.
This is the first prospective, race‐stratified study in advanced prostate cancer demonstrating important trends in outcomes previously only observed in retrospective reports. These results demonstrate the feasibility of this approach in a multicenter setting and establish important preliminary data with regard to differences in toxicity profiles and predictive biomarkers by race.
Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized ...trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS).
Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score GS ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05.
A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61).
NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.
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