Author
Mohammad Hirmand
Bio: Mohammad Hirmand is an academic researcher from Medivation. The author has contributed to research in topics: Enzalutamide & Prostate cancer. The author has an hindex of 17, co-authored 31 publications receiving 5234 citations.
Papers
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TL;DR: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy, and was shown with respect to all secondary end points.
Abstract: Background Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor–signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. Methods In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. Results The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for de...
3,866 citations
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TL;DR: The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease.
1,024 citations
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TL;DR: The CTC0 and CTC conversion end points are robust and meaningful response end points for early-phase metastatic castration-resistant prostate cancer clinical trials and have the highest discriminatory power for overall survival.
Abstract: PurposeMeasures of response that are clinically meaningful and occur early are an unmet need in metastatic castration-resistant prostate cancer clinical research and practice. We explored, using individual patient data, week 13 circulating tumor cell (CTC) and prostate-specific antigen (PSA) response end points in five prospective randomized phase III trials that enrolled a total of 6,081 patients—COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1—ClinicalTrials.Gov identifiers: NCT00638690, NCT00974311, NCT01193257, NCT01193244, and NCT01605227, respectively.MethodsEight response end points were explored. CTC nonzero at baseline and 0 at 13 weeks (CTC0); CTC conversion (≥ 5 CTCs at baseline, ≤ 4 at 13 weeks—the US Food and Drug Administration cleared response measure); a 30%, 50%, and 70% decrease in CTC count; and a 30%, 50%, and 70% decrease in PSA level. Patients missing week-13 values were considered nonresponders. The discriminatory strength of each end point with respect to overall survival in eac...
168 citations
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TL;DR: The AFFIRM trial as mentioned in this paper showed that enzalutamide significantly increased overall survival compared with placebo in patients with metastatic castration-resistant prostate cancer after progression with docetaxel treatment.
Abstract: Summary Background In the AFFIRM trial of patients with metastatic castration-resistant prostate cancer after progression with docetaxel treatment, enzalutamide significantly increased overall survival compared with placebo. Here we present the prospectively defined analyses of some secondary endpoints, including occurrence of skeletal-related events, measures of pain control, and patient-reported health-related quality of life (HRQoL). Methods In this phase 3, double-blind trial, patients were randomly assigned (2:1) to receive enzalutamide 160 mg/day or placebo orally, stratified by ECOG baseline performance status (0 or 1 vs 2) and mean pain score (Brief Pain Inventory-Short Form [BPI-SF] question 3 worst pain, score ≤3 vs ≥4). Secondary endpoints were time to first skeletal-related event (radiation therapy or surgery to bone, clinically apparent pathological bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain); change from baseline to week 13 in pain severity and interference; pain palliation and progression at week 13; time to pain progression; overall improvement in HRQoL; improvements in HRQoL domains; and time to HRQoL deterioration. Analysis was done on the intention-to-treat population for each endpoint. AFFIRM is registered with ClinicalTrials.gov, number NCT00974311. Findings Median time to first skeletal-related event in the enzalutamide (n=800) and placebo (n=399) groups was 16·7 months (95% CI 14·6 to 19·1) and 13·3 months (95% CI 9·9 to not yet reached), respectively (hazard ratio [HR] 0·69 [95% CI 0·57–0·84]; p=0·0001). Pain progression at week 13 occurred in 174 (28%) of 625 evaluable patients in the enzalutamide group versus 101 (39%) of 259 patients in the placebo group (difference −11·2%, 95% CI −18·1 to −4·3; p=0·0018). Median time to pain progression was not yet reached in the enzalutamide group (95% CI not yet reached to not yet reached) versus 13·8 (13·8 to not yet reached) months in the placebo group (HR 0·56 [95% CI 0·41 to 0·78]; p=0·0004). Mean treatment effects for pain severity (mean change from baseline in the enzalutamide group −0·15, 95% CI −0·28 to −0·02, vs placebo 0·50, 0·29 to 0·70; difference −0·65, 95% CI −0·89 to −0·41; p vs 0·74, 0·47 to 1·00; respectively, difference −0·74, 95% −1·06 to −0·43; p vs 3·7 months, 95% CI 3·0–4·2; HR 0·45, 95% CI 0·37–0·55; p Interpretation Our results show that, in addition to improving overall survival, enzalutamide improves wellbeing and everyday functioning of patients with metastatic castration-resistant prostate cancer. Funding Astellas Pharma and Medivation.
162 citations
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TL;DR: MDV3100, a novel ARSI, significantly improves OS in men with postdocetaxel-treated CRPC reducing the risk of death by 37% relative to placebo and recommended the phase III AFFIRM trial be unblinded.
Abstract: LBA1 Background: MDV3100, a novel androgen receptor signaling inhibitor (ARSI), competitively inhibits binding of androgens to the androgen receptor (AR), inhibits AR nuclear translocation, and inhibits association of the AR with DNA (Tran et al, Science. 2009;324:787). MDV3100 was selected for development based on activity in prostate cancer model systems with overexpressed AR, and was active in a phase I-II trial enrolling pre- and post-chemotherapy treated patients with progressive castration resistant disease (CRPC) (Scher et al, Lancet. 2010;375:1437). The AFFIRM trial evaluated whether MDV3100 could prolong overall survival (OS) in men with CRPC who progressed following docetaxel-based chemotherapy. Methods: In this randomized, double-blind, placebo-controlled, multinational phase III study (NCT00974311), patients who had received ≤ 2 regimens of docetaxel-based chemotherapy were randomized 2:1 to MDV3100 160 mg/day or placebo. Treatment with corticosteroids was allowed but not required. Patients we...
114 citations
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TL;DR: The number of cancer survivors continues to increase because of both advances in early detection and treatment and the aging and growth of the population and for the public health community to better serve these survivors, the American Cancer Society and the National Cancer Institute collaborate to estimate the number of current and future cancer survivors.
Abstract: The number of cancer survivors continues to increase because of both advances in early detection and treatment and the aging and growth of the population. For the public health community to better serve these survivors, the American Cancer Society and the National Cancer Institute collaborate to estimate the number of current and future cancer survivors using data from the Surveillance, Epidemiology, and End Results cancer registries. In addition, current treatment patterns for the most prevalent cancer types are presented based on information in the National Cancer Data Base and treatment-related side effects are briefly described. More than 15.5 million Americans with a history of cancer were alive on January 1, 2016, and this number is projected to reach more than 20 million by January 1, 2026. The 3 most prevalent cancers are prostate (3,306,760), colon and rectum (724,690), and melanoma (614,460) among males and breast (3,560,570), uterine corpus (757,190), and colon and rectum (727,350) among females. More than one-half (56%) of survivors were diagnosed within the past 10 years, and almost one-half (47%) are aged 70 years or older. People with a history of cancer have unique medical and psychosocial needs that require proactive assessment and management by primary care providers. Although there are a growing number of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based resources are needed to optimize care. CA Cancer J Clin 2016;66:271-289. © 2016 American Cancer Society.
5,516 citations
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TL;DR: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy, and was shown with respect to all secondary end points.
Abstract: Background Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor–signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. Methods In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. Results The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for de...
3,866 citations
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University of Michigan1, Massachusetts Institute of Technology2, Harvard University3, Memorial Sloan Kettering Cancer Center4, University of Washington5, The Royal Marsden NHS Foundation Trust6, Institute of Cancer Research7, Cornell University8, Brigham and Women's Hospital9, Beth Israel Deaconess Medical Center10, University of Washington Medical Center11, University of Trento12, Wayne State University13, Johns Hopkins University14
TL;DR: This cohort study provides clinically actionable information that could impact treatment decisions for affected individuals and identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF.
2,713 citations
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National Health Service1, University of Oslo2, Karolinska Institutet3, University of Bergen4, Queen's University Belfast5, Curie Institute6, Umeå University7, Mount Vernon Hospital8, Leeds Teaching Hospitals NHS Trust9, Cancer Research UK10, Norwegian University of Science and Technology11, Comenius University in Bratislava12, University of São Paulo13, Algeta14, Bayer Corporation15, Tulane University16
TL;DR: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival and was associated with low myelosuppression rates and fewer adverse events.
Abstract: efit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. Conclusions In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Phar -
2,614 citations
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Oregon Health & Science University1, Duke University2, Memorial Sloan Kettering Cancer Center3, University of Paris-Sud4, University of Washington5, Guy's and St Thomas' NHS Foundation Trust6, Institute of Cancer Research7, University of California, Berkeley8, University Health Network9, Nippon Medical School10, Charité11, Astellas Pharma12, Université de Montréal13, Harvard University14, University of Alberta15, Cliniques Universitaires Saint-Luc16
TL;DR: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer.
Abstract: BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
2,426 citations