Enzalutamide (Xtandi) monotherapy induced striking declines in prostate-specific antigen (PSA) in a majority of patients with hormone-naive prostate cancer in a phase II trial, and this oral agent appears to have little effect on bone mineral density. If these findings are confirmed in a phase III trial, then enzalutamide may be an alternative to androgen deprivation therapy in recurrent and metastatic prostate cancer with fewer side effects.

Effective Monotherapy
In a phase II trial of men who have not yet had hormone therapy (ADT), Enzalutamide (Xtandi) achieved marked PSA responses and PSA declines without some of the negative side effects associated with ADT. According to Matthew R. Smith, MD, PhD, of Massachusetts General Hospital in Boston the results of this trial compare favorably with the data for androgen deprivation therapy. In contrast with androgen deprivation therapy, men treated with Xtandi had stable bone mineral density and only modest changes in serum triglycerides, both of these being significant issues in ADT.

According to Smith, “ The beneficial effects seen in this phase II trial are consistent with those seen with potent

[androgen deprivation therapy] inhibition, and support the role of enzalutamide as monotherapy in prostate cancer.”

Currently Xtandi is approved for use after Docetaxil (chemotherapy). There are a number of on-going trials evaluating the potential of using Xtandi both in the castrate resistant pre-chemo state and in men with advanced prostate cancer who are also ADT naive.

ADT is considered the mainstay of treatment for recurrent or metastatic prostate cancer, the side effects can be difficult for men to tolerate. Side effects include hot flashes, fatigue, loss of libido and erectile function, increased risk of bone mineral density loss, decreased muscle mass, and decreased insulin sensitivity that increases the risk of diabetes and cardiovascular disease. Bicalutamide, sometime referred to as ADT light was evaluated as an alternative to androgen deprivation therapy, and although the drug seems to have little or no effect on bone mineral density, it also appears to be less effective than standard androgen deprivation therapy.

About This Study
Ths was a phase II open-label, multicenter study designed to evaluated Xtandi as a monotherapy in men with hormone-naive advanced prostate cancer for which androgen deprivation therapy is indicated. All the men in the study had testosterone levels ? 230 ng/mL, PSA ? 2 ng/mL, and life expectancy of at least 12 months.

Men were treated with Xtandi monotherapy for 25 weeks. At that point, a primary efficacy analysis was performed. Men deemed eligible could continue on therapy. The study included 67 men, with a median age of 73 years, mean body mass index of 22.6 kg/m2, median baseline PSA of 18.2 ng/mL, and median duration of prostate cancer since diagnosis of 1 year; 50% had Gleason 7 scores and 25% had Gleason 8 to 10 scores at entry. Approximately 38% had metastasis at study entry, and about one-third had had a prior prostatectomy.

The primary endpoint was PSA response (at least an 80% decline in PSA level). Monotherapy with enzalutamide achieved marked and rapid PSA declines in 92.5% of men. Median PSA decrease was –99.6%. A total of 62 of 67 (92.5%) achieved the primary endpoint of PSA decline > 80% at week 25, including patients with and without metastasis at baseline. Four of five patients categorized as non-responders were actually men who withdrew from the study before response was evaluable.

Among 16 patients evaluable for objective responses with measurable disease, the complete plus partial response rate was 50%. Dr. Smith said that the data on durability of response will be included in the full publication of the trial’s results, but he did not have those data at the time of the Annual Meeting.

Adverse Effects
The expected rate of decline in bone mineral density is 3% to 5% during the first year of androgen deprivation therapy. In this study, no significant changes in bone mineral density were observed after 25 weeks of treatment with enzalutamide. In fact, bone mineral density increased at the femoral neck by about 0.4%.
After 25 weeks of enzalutamide monotherapy, mean body mass index decreased by 4.2%, and body fat increased by 6.9%. Moderate increases were seen in serum triglycerides (6.5%) and total cholesterol levels (+4.6%), and these changes compare favorably with the effect of androgen deprivation therapy on these parameters.

1. Smith MR, Borre M, Rathenborg P, et al: Efficacy and safety of enzalutamide monotherapy in hormone-naive prostate cancer. 2013 ASCO Annual Meeting. Abstract 5001. Presented June 3, 2013. Note- Dr. Smith has served in a consultant or advisory role for Astellas Pharma and has received honoraria from Medivation.

Joel T. Nowak, M.A., M.S.W.