Enzalutamide Promising in Hormone-Naive Prostate Cancer

TON - September 2013 Vol 6 No 8 — September 23, 2013

Promising results were obtained with enzalutamide monotherapy in patients with hormone-naive prostate cancer. The drug prevented biochemical failure in more than 90% of patients enrolled in a phase 2 trial, and enzalutamide appears to have an improved adverse event profile compared with standard androgen deprivation therapy (ADT). A phase 3 trial will be needed to determine the role of enzalutamide vis-à-vis standard ADT.

Enzalutamide, an oral androgen receptor antagonist, is approved by the US Food and Drug Administration for the treatment of metastatic castration-resistant prostate cancer that progresses on docetaxel. The phase 2 trial, reported at the 2013 American Society of Clinical Oncology Annual Meeting, sought to evaluate the role of this novel agent earlier in the course of disease.

“Enzalutamide monotherapy achieved high PSA responses and PSA declines in men with hormone-naive prostate cancer. We believe the results of this trial compare favorably with ADT. By contrast with ADT, patients treated with enzalutamide had stable bone mineral density (BMD) and only modest changes in serum triglycerides. The effects seen in this phase 2 trial are consistent with those seen with potent ADT inhibition, and support the role of enzalutamide as monotherapy in prostate cancer,” stated Matthew R. Smith, MD, Dana-Farber Cancer Institute and Massachusetts General Hospital in Boston.

ADT is considered the mainstay of treatment for recurrent or metastatic prostate cancer, but men find the side effects difficult to tolerate, including frequent hot flashes, fatigue, loss of libido and erectile function, gynecomastia, increased risk of BMD loss, decreased muscle mass, and decreased insulin sensitivity. Some of these side effects are risk factors for diabetes mellitus and cardiovascular disease. It would be desirable to have an effective therapy with fewer adverse events, Smith told listeners.

The study included patients with hormone-naive prostate cancer for which ADT is indicated. At baseline, patients had testosterone levels ≥230 ng/mL, prostate-specific antigen (PSA) ≥2 ng/mL, and a life expectancy of at least 12 months.

The men received enzalutamide monotherapy for 25 weeks; then an analysis of primary efficacy was performed. Patients deemed eligible could continue on therapy. The study included 67 men, with a median age of 73 years, median body mass index (BMI) 26.2 kg/m2, median baseline PSA 18.2 ng/mL, and median duration of prostate cancer since diagnosis of 1 year; 51% had a Gleason score of 7, and 24% had a Gleason score ≥8 at entry. At study entry, 39% had metastasis, and more than one-third had prior prostatectomy.

Enzalutamide monotherapy achieved marked and rapid PSA declines in 92.5% of patients; median PSA decrease was –99.6%; and 62/67 (92.5%) achieved the primary end point of PSA decline ≥80% at week 25, regardless of the presence of metastasis at baseline. Four of 5 patients deemed nonresponders were actually withdrawals prior to evaluating response. Among 16 patients evaluable for objective responses with measurable disease, complete response plus partial response was 50%.

Although BMD declines of 3% to 4% are observed during the first year of ADT, no significant changes in BMD were found after 25 weeks of treatment with enzalutamide. In fact, slight increases in BMD were observed at the femoral neck and other sites.

After 25 weeks of enzalutamide monotherapy, mean BMI 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%), but Smith noted that these are smaller increases than occur with ADT.

Discussant’s Comments
The study was positive, with a high rate of PSA decline and an improved side effect profile for enzalutamide compared with ADT, said formal discussant Michael Carducci, MD, of the Johns Hopkins School of Medicine in Baltimore, Maryland.

Enzalutamide is 1 of 6 new drugs approved for metastatic castration-resistant prostate cancer, and the use of each of these drugs will also be studied earlier in the course of disease, Carducci continued. He said that advances in survival will come from learning how to optimize sequencing of the new drugs as well as older therapies. The emphasis will be on how best to combine agents. Several studies are under way to examine this question. —AG

Reference
Smith MR, Borre M, Rathenborg P, et al. Efficacy and safety of enzalutamide (ENZA) monotherapy in hormone-naive prostate cancer (HNPC). J Clin Oncol. 2013;31(suppl):Abstract 5001. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

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