Despite expanding treatment options for castration-resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells' natural ability to develop iterative resistance.
Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K-Akt pathway. Thus inhibition of AR signalling and PI3K-Akt-mTOR (a downstream mediator of the PI3K-Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K-Akt-mTOR. The AR pathway and the PI3K-Akt-mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K-Akt-mTOR inhibitors are in development and likely will be tested in combination in CRPC.
OBJECTIVES:To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration-resistant prostate cancer (CRPC). To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC.
PATIENTS AND METHODS:A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC. The primary endpoint was a composite of prostate-specific antigen (PSA) level and measurable disease response by standard criteria. This single-stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥40% from a response rate of ≤ 20%, as expected for bicalutamide alone (α= 0.10, power = 0.90).
RESULTS:In total, 36 men were enrolled, with a median (range) age of 68 (60-72) years and median (range) baseline PSA level of 22.2 (8.4-121.3) ng/mL, and 89% had metastatic disease. There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months. There were two patients with a confirmed PSA level decline ≥50%. The median (interquartile range) time to progression was 8.7 (7.9-15.9) weeks. The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients.
CONCLUSION: The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.
Written by:
Nakabayashi M, Werner L, Courtney KD, Buckle G, Oh WK, Bubley GJ, Hayes JH, Weckstein D, Elfiky A, Sims DM, Kantoff PW, Taplin ME. Are you the author?
Lank Center for Genitourinary Oncology Division of Medical Oncology, Department of Medicine and Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School Beth Israel Deaconess Medical Center, Boston, MA; Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY New Hampshire Oncology Hematology, Hooksett, NH, USA.
Reference: BJU Int. 2012 Aug 29. Epub ahead of print.
doi: 10.1111/j.1464-410X.2012.11456.x
PubMed Abstract
PMID: 22928480
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