A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer

作者：Chow Helen; Ghosh Paramita M; White Ralph deVere; Evans Christopher P; Dall'Era Marc A; Yap Stanley A; Li Yueju; Beckett Laurel A; Lara Primo N; Pan Chong Xian^*

来源：Cancer, 2016, 122(12): 1897-1904.

DOI：10.1002/cncr.29927

• castration-resistant prostate cancer
• everolimus
• bicalutamide
• mammalian target of rapamycin (mTOR)
• urology

BACKGROUNDThe 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.
METHODSPatients 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 error of .05 (1-sided) if the combination had a PSA response rate of 50% versus a historic rate of 25% with bicalutamide alone.
RESULTSTwenty-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.
CONCLUSIONSThe 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.
The combination of bicalutamide and everolimus achieved a prostate-specific antigen response rate of 75% (95% confidence interval, 0.53-0.90) compared with the historical control of 25% with bicalutamide alone in 24 bicalutamide-naive patients with castration-resistant prostate cancer.

• 出版日期2016-6-15