Combined treatment with bicalutamide and everolimus has “encouraging efficacy” in patients with bicalutamide-naïve castration-resistant prostate cancer (CRPC), researchers concluded from a phase 2 study.

The study, led by Chong-Xian Pan, MD, PhD, of the University of California Davis, and colleagues, included 24 men with progressive CRPC and a mean serum testosterone levels at study entry of 43.4 ng/dL. None of the patients had prior treatment with either bicalutamide (except to prevent flare) or everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) pathway.

The men were prescribed oral bicalutamide 50 mg and oral everolimus 10 mg, both once daily, on a 4-week cycle. The primary endpoint was PSA response, defined as a 30% or greater reduction in PSA from baseline.

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The mean length of treatment was 8 cycles. Of the 24 patients, 18 (75%) had a PSA response and 15 (62.5%) had a PSA decrease of 50% or greater, the investigators reported online ahead of print in Cancer. The cohort had a mean overall survival time of 28 months; 14 patients experienced grade 3 (13 patients) or 4 (1 patient) adverse events attributable to treatment.

Dr Pan’s team concluded that combination therapy with bicalutamide and everolimus “represents a promising new era of treatment” for men with bicalutamide-naïve CRPC, and stated that a randomized phase 3 trial with everolimus in combination with anti-androgen therapy is warranted.

“However, because of significant toxicity, modification of the study design is needed,” they added. “One option is to reduce the everolimus dose, because toxicity improved in the vast majority of patients after the everolimus dose, but not the bicalutamide dose, was reduced.”

The researchers noted that overexpression of androgen receptors (AR) and AR mutation are among the mechanisms proposed to explain castration resistance. A previous study showed that inhibiting the mTOR signaling pathway also up-regulated the AR signaling pathway. “This compensatory mechanism explained why an mTOR inhibitor alone has little therapeutic effect in CRPC.” Results also showed that bicalutamide inhibited AR transcriptional activity stimulated by rapamycin without affecting inhibition of the mTOR pathway. On the basis of these findings and those from other studies, Dr Pan and colleagues hypothesized that simultaneous blockade of the mTOR and AR pathways would be synergistic against CRPC cells.