PMID- 27019001 OWN - NLM STAT- MEDLINE DCOM- 20170315 LR - 20220419 IS - 1097-0142 (Electronic) IS - 0008-543X (Print) IS - 0008-543X (Linking) VI - 122 IP - 12 DP - 2016 Jun 15 TI - A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer. PG - 1897-904 LID - 10.1002/cncr.29927 [doi] AB - BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is up-regulated in castration-resistant prostate cancer (CRPC). Nevertheless, inhibition of mTOR is ineffective in inducing apoptosis in prostate cancer cells, likely because of the compensatory up-regulation of the androgen receptor (AR) pathway. METHODS: Patients who were eligible for this study had to have progressive CRPC with serum testosterone levels <50 ng/dL. No prior bicalutamide (except to prevent flare) or everolimus was allowed. Treatment included oral bicalutamide 50 mg and oral everolimus 10 mg, both once daily, with a cycle defined as 4 weeks. The primary endpoint was the prostate-specific antigen (PSA) response (>/=30% reduction) from baseline. A sample size of 23 patients would have power of 0.8 and an alpha error of .05 (1-sided) if the combination had a PSA response rate of 50% versus a historic rate of 25% with bicalutamide alone. RESULTS: Twenty-four patients were enrolled. The mean age was 71.1 years (range, 53.0-87.0 years), the mean PSA level at study entry was 43.4 ng/dL (range, 2.5-556.9 ng/dL), and the mean length of treatment was 8 cycles (range, 1.0-23.0 cycles). Of 24 patients, 18 had a PSA response (75%; 95% confidence interval [CI], 0.53-0.90), whereas 15 (62.5%; 95% CI, 0.41-0.81) had a PSA decrease >/=50%. The median overall survival was 28 months (95% CI, 14.1-42.7 months). Fourteen patients (54%; 95% CI, 0.37-0.78) developed grade 3 (13 patients) or grade 4 (1 patient with sepsis) adverse events that were attributable to treatment. CONCLUSIONS: The combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide-naive CRPC, thus warranting further investigation. A substantial number of patients experienced everolimus-related toxicity. Cancer 2016;122:1897-904. (c) 2016 American Cancer Society. CI - (c) 2016 American Cancer Society. FAU - Chow, Helen AU - Chow H AD - Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis, Sacramento, California. FAU - Ghosh, Paramita M AU - Ghosh PM AD - Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California. AD - Veterans Affairs Northern California Health Care System-Mather, Mather, California. AD - Department of Urology, University of California Davis, Sacramento, California. FAU - deVere White, Ralph AU - deVere White R AD - Department of Urology, University of California Davis, Sacramento, California. FAU - Evans, Christopher P AU - Evans CP AD - Department of Urology, University of California Davis, Sacramento, California. FAU - Dall'Era, Marc A AU - Dall'Era MA AD - Department of Urology, University of California Davis, Sacramento, California. FAU - Yap, Stanley A AU - Yap SA AD - Department of Urology, University of California Davis, Sacramento, California. FAU - Li, Yueju AU - Li Y AD - Department of Public Health Sciences, University of California, Davis, California. FAU - Beckett, Laurel A AU - Beckett LA AD - Department of Public Health Sciences, University of California, Davis, California. FAU - Lara, Primo N Jr AU - Lara PN Jr AD - Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis, Sacramento, California. FAU - Pan, Chong-Xian AU - Pan CX AD - Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis, Sacramento, California. AD - Veterans Affairs Northern California Health Care System-Mather, Mather, California. AD - Department of Urology, University of California Davis, Sacramento, California. LA - eng GR - P30 CA093373/CA/NCI NIH HHS/United States GR - R01 CA133209/CA/NCI NIH HHS/United States GR - R01 CA185509/CA/NCI NIH HHS/United States GR - U10 CA180846/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160328 PL - United States TA - Cancer JT - Cancer JID - 0374236 RN - 0 (AR protein, human) RN - 0 (Androgen Antagonists) RN - 0 (Anilides) RN - 0 (Nitriles) RN - 0 (Receptors, Androgen) RN - 0 (Tosyl Compounds) RN - 9HW64Q8G6G (Everolimus) RN - A0Z3NAU9DP (bicalutamide) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Aged MH - Aged, 80 and over MH - Androgen Antagonists/administration & dosage MH - Anilides/administration & dosage MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Everolimus/administration & dosage MH - Humans MH - Male MH - Middle Aged MH - Nitriles/administration & dosage MH - Prostatic Neoplasms, Castration-Resistant/*drug therapy MH - Receptors, Androgen/metabolism MH - TOR Serine-Threonine Kinases/antagonists & inhibitors MH - Tosyl Compounds/administration & dosage PMC - PMC4892938 MID - NIHMS776181 OTO - NOTNLM OT - bicalutamide OT - castration-resistant prostate cancer OT - everolimus OT - mammalian target of rapamycin (mTOR) OT - urology EDAT- 2016/03/29 06:00 MHDA- 2017/03/16 06:00 PMCR- 2017/06/15 CRDT- 2016/03/29 06:00 PHST- 2015/10/21 00:00 [received] PHST- 2015/12/28 00:00 [revised] PHST- 2016/01/04 00:00 [accepted] PHST- 2016/03/29 06:00 [entrez] PHST- 2016/03/29 06:00 [pubmed] PHST- 2017/03/16 06:00 [medline] PHST- 2017/06/15 00:00 [pmc-release] AID - 10.1002/cncr.29927 [doi] PST - ppublish SO - Cancer. 2016 Jun 15;122(12):1897-904. doi: 10.1002/cncr.29927. Epub 2016 Mar 28.