Combination therapy with bicalutamide and everolimus resulted in promising responses in a phase II trial of patients with castration-resistant prostate cancer (CRPC), though a substantial proportion of patients experienced everolimus-related toxicities.
Second-line therapy with an androgen receptor modulator such as bicalutamide generally has a response rate around 25%, and response durations of only a few months. Most patients will develop resistance to these treatments. “Therefore, there is a substantial need to improve upon new treatment options,” wrote study authors led by Chong-Xian Pan, MD, PhD, of the University of California, Davis.
Previous research has suggested that combining bicalutamide with an mTOR inhibitor could yield better results. The new phase II trial included 24 CRPC patients with a mean age of 71.1 years; patients were treated with oral bicalutamide and oral everolimus once daily. The results were published online ahead of print in Cancer.
A total of 18 patients (75%) had a prostate-specific antigen (PSA) response, defined as a reduction of at least 30% from baseline. The median duration of response for those patients was 5.6 months, with a range from 0 to 21.6 months; a previously reported historic cohort treated with bicalutamide alone had a median duration of response of 3.2 months. Fifteen patients (62.5%) had a PSA drop of at least 50%.
Four patients had a partial response and one had a complete response to the therapy. Another 14 patients had stable disease, while four patients had progressive disease and one did not have an available response result.
As of data cutoff in February 2015, 11 patients (46%) were still alive. Two patients died of other causes, and 11 died of progressive disease. The median overall survival was 28 months, and the median progression-free survival was 9.4 months. Again, this outperformed the historic cohort, which had a median PFS of 5.8 months with bicalutamide alone.
A total of 13 patients (54.2%) experienced a grade 3 adverse event (AE), and one had a grade 4 toxicity. Most hematologic toxicities were mild, though there were at least one episode of grade 3 neutropenia, anemia, and thrombocytopenia, and one patient had grade 4 non-neutropenic sepsis. The most common non-hematologic grade 3 AEs included oral mucositis in four patients and hyperglycemia in two patients. The authors noted that those symptoms improved following a reduction in the everolimus dose.
“Combination therapy with everolimus and bicalutamide represents a promising new area of treatment for patients with bicalutamide-naive CRPC,” the authors concluded, adding that a phase III trial is now warranted. However, the toxicities seen in this phase II trial suggest that a change in study design is needed, possibly with a reduced everolimus dose. Newer anti-androgen therapies including abiraterone and enzalutamide could also be considered.