Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes ...of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m
for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio HR, 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.
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.
In spite of the development of new treatments for late stage prostate cancer, significant challenges persist to match individuals with effective targeted therapies. Genomic classification using ...high-throughput sequencing technologies has the potential to achieve this goal and make precision medicine a reality in the management of men with castrate-resistant prostate cancer. This chapter reviews some of the most recent studies that have resulted in significant progress in determining the landscape of somatic genomic alterations in this cohort and, more importantly, have provided clinically actionable information that could guide treatment decisions. This chapter reviews the current understanding of common alterations such as alterations of the androgen receptor and PTEN pathway, as well as ETS gene fusions and the growing importance of PARP inhibition. It also reviews recent studies that characterize the evolution to neuroendocrine tumors, which is becoming an increasingly important clinical problem. Finally, this chapter reviews recent innovative studies that characterize the compelling evolutionary history of lethal prostate cancer evidenced by polyclonal seeding and interclonal cooperation between metastasis and the importance of tumor clone dynamics measured serially in response to treatment. The genomic landscape of late stage prostate cancer is becoming better defined, and the prospect for assigning clinically actionable data to inform rationale treatment for individuals with this disease is becoming a reality.
Abstract Background Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. Objective To directly assess whether germline mutations in these three genes ...distinguish lethal from indolent PCa and whether they confer any effect on age at death. Design, setting, and participants A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. Outcome measurements and statistical analysis Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively. Results and limitations The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p = 0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61–65 yr, 66–70 yr, 71–75 yr, and over 75 yr, respectively, p = 0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6–10 yr, and > 10 yr after a PCa diagnosis, respectively, p = 0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio = 2.13, 95% confidence interval: 1.24–3.66, p = 0.004). A limitation of this study is that other DNA repair genes were not analyzed. Conclusions Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. Patient summary Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.
Radium 223 dichloride (radium-223) is an alpha particle–emitting bone-directed therapy that prolongs overall survival in men with bone-predominant metastatic castration-resistant prostate cancer ...(mCRPC). Docetaxel is an antimicrotubule cytotoxic agent that improves survival in mCRPC. We investigated whether combining these potentially cross-sensitising agents to dually target tumour and bone would be safe and effective.
Phase 1 was a dose escalation study to define a recommended phase 2 dose (RP2D) of docetaxel and radium-223. In phase 2a, patients were randomised 2:1 to the recommended combination regimen or docetaxel at a dose of 75 mg/m2 every 3 weeks (q3w). Patients with bone-predominant mCRPC were eligible. End-points were safety, efficacy and treatment-related changes in serum and imaging biomarkers.
Twenty patients were enrolled in phase 1; 53 patients were randomised in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m2 q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% vs 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers.
Radium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced antitumour activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted. ClinicalTrials.gov number: NCT01106352.
•Radium-223 55 kBq/kg every six weeks × 5 and docetaxel 60 mg/m2 every three weeks (q3w) × 10 were recommended in phase 1.•Combination was well tolerated in the randomised phase 2a part of the study.•Combination presented no more safety concerns than docetaxel alone at a dose of 75 mg/m2 q3w.•Exploratory efficacy data suggested enhanced antitumour activity for the combination therapy.
EA8212 BRIDGE is a phase 3 randomized trial comparing BCG vs GemDoce for BCG naïve high-risk non–muscle-invasive bladder cancer. This article provides an explanation for the rationale of the clinical ...trial and details the study design.
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Background: Genomic profiling of patients (pts) with mCRPC is becoming more widely utilized to assist in prognosis and treatment. Liquid biopsies offer a non-invasive method of ...assessing gene alterations but questions remain regarding their validity, as well as the association of these alterations with relevant clinical outcomes. Methods: We present a retrospective analysis of 82 pts who underwent genomic profiling at the onset of mCRPC using the Guardant360 cfDNA assay. Clinical outcomes data was recorded in a structured note in the electronic medical record that allowed discrete data elements to be stored and analyzed. Patients received standard treatment with Abiraterone (Abi) and Enzalutamide (Enza) as well as chemotherapy. Relevant clinical outcome endpoints included overall survival (OS) and time on treatment with Abi and Enza (TT). These endpoints were compared between patients grouped by their gene alterations and treatment. Univariate and multivariate association analyses were performed. Results: The structured note was found to be valuable in capturing relevant discrete clinical outcomes data for detailed analysis. Median OS for the 82 pts was 58 months. 15 pts had insufficient cfDNA to perform the assay and these pts had a significantly longer OS than the 67 pts with sufficient cfDNA (median not reached vs 36 months, p = 0.004). The most commonly altered genes were AR and TP53 with 45% pts having alterations in both genes. Our analysis showed significantly shorter OS with BRAF (24 months, p = 0.008) and NF1 (20 months, p = 0.036) alterations. However, the significance was lost after multiple hypothesis correction. We observed that pts with co-occurrence of AR and BRAF had a significantly shorter OS (18.7 months, p = 0.031). BRCA2 mutations were observed in 9 pts and were associated with a significantly shorter TT (23 vs 38 months, p = 0.022) but lost significance after multiple hypothesis correction. Patients who received Abi followed by Enza had a significantly longer TT compared to pts who received the reverse sequence (38 months vs 23 months, p = 0.02). Conclusions: In this retrospective analysis, we did not identify any significant associations between specific gene alterations and relevant clinical outcomes. We observed a trend of shorter OS with BRAF and NF1 alterations and a shortened OS with co-occurrence of AR and BRAF alterations. These associations will require validation in a larger study. The presence of sufficient DNA to perform the assay was associated with shorter OS. The treatment sequence of Abi followed by Enza showed longer TT than the reverse sequence. The structured note allowed capture of relevant clinical outcomes data and is currently being utilized in a larger prospective genomic study of mCRPC.
Abstract Objective A conceptual framework for patient-reported outcomes (PROs) is a structured representation of outcome concepts and issues. Our aim was to develop a conceptual framework of PROs for ...hormone-refractory prostate cancer (HRPC) to support measurement clarity. Methods Relevant outcome issues were identified from review of recent clinical trials. This provided content for an interview with 15 metastatic HRPC patients and a survey of 10 practitioners. All participants were asked about the relevance and importance of 26 outcomes and were allowed to nominate new outcomes. Practitioners were also asked to determine which outcomes endorsed by patients were attributable to the disease (symptoms) versus treatment (side effects). Analyses of archived clinical trial data were used to verify and augment the interview and survey results. Results Patients endorsed 11 concerns as relevant and important to HRPC including general pain, bone pain, urinary problems, fatigue, appetite loss, constipation, erectile dysfunction, peripheral neuropathy, diarrhea, PSA anxiety, and changes in self image. Practitioner judgments helped classify each concern into one of four categories, disease symptom, treatment side effect, both symptom and side effect, or psychological concern. Additionally, patients endorsed (and practitioners confirmed) the relevance and importance of several general domains of quality of life. Analyses of archived data confirmed the importance of these issues and suggested two additional concerns. Conclusion Findings were used to propose a conceptual framework of PROs for metastatic HRPC. Such frameworks can be used to help specify targets for assessment in clinical studies such as treatment trials.
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Background: Significant lack of treatment (Tx) intensification is seen in clinical practice for pts with mHSPC until progression to mCRPC. The TRUMPET registry enabled a post-hoc analysis of ...clinical outcomes in pts with mCRPC, initially diagnosed with de novo mHSPC vs nmHSPC. Methods: TRUMPET, a prospective, observational study of US pts with CRPC, enrolled male adults (03/2015-09/2018) who began first or second-line Tx for M0/M1 CRPC. For this post hoc, pts with M1 CRPC at enrollment initially diagnosed with de novo mHSPC (clinical TNM1 stage) were compared to M1 CRPC pts initially diagnosed with nmHSPC (clinical TNM0 stage). Clinical outcomes (radiographic progression-free survival rPFS, prostate specific antigen PSA progression, time to opiate initiation OI, mortality) were analysed with Kaplan–Meier and Cox proportional hazards models. An exploratory subanalysis investigated outcomes in de novo mHSPC pts who received Tx intensification (docetaxel or abiraterone) with androgen-deprivation therapy (ADT) as primary Tx prior to mCRPC vs pts who did not. Results: M1 CRPC pts initially diagnosed with de novo mHSPC (n = 199) or nmHSPC (n = 254) were included; median age: 70.0 vs 73.0 years, duration from initial PC diagnosis to baseline mCRPC visit: 1.62 vs 6.72 years, PSA at PC diagnosis: 113.1 vs 10.1 ng/mL, Gleason score: 9.0 vs 8.0, respectively. In the de novo mHSPC and nmHSPC groups, initial CRPC Tx was chemotherapy in 9.0% vs 5.9% of pts, novel hormonal therapy (enzalutamide or abiraterone) in 55.3% vs 59.1%, immunotherapy in 35.2% vs 42.9%, respectively. No differences were seen in rPFS or PSA progression (table). The de novo mHSPC group showed a trend toward shorter time to OI and significantly increased risk of mortality (37%) with 6.6 months shorter median survival vs nmHSPC. The subanalysis included 44 (22.1%) de novo mHSPC pts who received Tx intensification with ADT at initial diagnosis. A trend towards improved survival was seen in the Tx-intensified vs nonintensified subgroup (median time to death 95%CI; 47.7 months 22.18, NE vs 37.3 months 28.35, 43.01). Conclusions: At mCRPC diagnosis, pts with de novo mHSPC have significantly higher mortality risk than pts with nmHSPC, indicating a need to delay progression of de novo mHSPC to mCRPC. The trend for improved survival benefit in pts with Tx-intensified de novo mHSPC further underlines the need for early Tx intensification. Table: see text
This study seeks to improve the understanding of treatment patterns and associated health-related quality of life (HRQoL), clinical outcomes and healthcare utilization in US patients with ...castration-resistant prostate cancer (CRPC).
Treatment Registry for Outcomes in CRPC Patients (TRUMPET) is a US-based, prospective, observational multicenter registry (NCT02380274) involving patients with CRPC and their caregivers. Patients initiating their first active treatment course will be enrolled from urology and medical oncology practices, with data captured up to 4 years.
Information on prescribing patterns, HRQoL, clinical outcomes and healthcare utilization will be collected.
TRUMPET will enable scientific understanding of disease management in terms of HRQoL, clinical outcomes and healthcare utilization in clinical practice for patients with CRPC.
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