Monotherapy with enzalutamide (Xtandi) achieved a “high PSA response rate and marked PSA decline” in patients with hormone-naïve prostate cancer after 6 months in a single-arm, multicenter phase II study.
CHICAGO-Monotherapy with enzalutamide (Xtandi) achieved a “high PSA response rate and marked PSA decline” in patients with hormone-naÃ¯ve prostate cancer after 6 months in a single-arm, multicenter phase II study, reported Matthew Raymond Smith, MD, PhD, of the Massachusetts General Hospital Cancer Center, Boston (abstract 5001). Efficacy was similar to castration, but in contrast with castration, bone mineral density (BMD) remained stable and metabolic variables, including fat body mass, lipid, and glycemic profiles, were not substantially impacted by enzalutamide over the 6-month study period.
Chemical structure of enzalutamide
Smith and colleagues at Massachusetts General and centers in Belgium, Denmark, and Germany assessed enzalutamide monotherapy in 67 patients with HNPC and noncastrate levels of testosterone (greater than or equal to 230 ng/dL). Patients with any stage HNPC (Eastern Cooperative Oncology Group performance status 0, life expectancy greater than 1 year) requiring hormonal therapy received enzalutamide at the approved dose of 160 mg daily for 25 weeks.
Smith said the rationale for the study was “an unmet need” for better monotherapy for patients with locally advanced prostate cancer. Although the antiandrogen bicalutamide is used to maintain quality of life relative to castration with a luteinizing hormone-releasing hormone analog (LHRHa), its efficacy as a monotherapy is limited, said Smith. Enzalutamide, an oral androgen receptor (AR) inhibitor with higher AR–binding affinity than bicalutamide, was approved in the United States in August 2012 based on positive results from the phase III AFFIRM trial. It is currently indicated for treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.
Primary endpoint in the present study was PSA response (greater than or equal to 80% post-treatment decline at week 25). Other endpoints were endocrine levels, pharmacokinetics, safety, and metabolic changes (body composition, bone biomarkers, lipids, and glycemic profiles). Median age of patients was 73 years (range, 48-86). Thirty-nine percent of patients (n = 26) had metastases, 36% (n = 24) had prior prostatectomy, and 24% (n = 16) had prior radiation therapy.
Enzalutamide levels reached steady state after about 4 wks. At week 25, PSA response was 93% (62/67; 95% CI, 86%–99%); median PSA decrease was –99.6%. “These post-treatment PSA responses were rapid, with near maximal decline seen by 10 weeks,” said Smith. Declines in PSA were similar for patients with and without metastatic disease at baseline.
Mean testosterone and estrogen increased 114% and 72%, respectively. Other endocrine increases were also observed by the investigators, highest of which was 185% for luteinizing hormone. Other endocrine increases were also observed by the investigators, highest of which was 185% for luteinizing hormone.
Mean changes in metabolic outcomes at week 25 included: –0.24% total body BMD, –4.15% lean body mass, 6.85% fat body mass, 14.75% bone alkaline phosphatase, 4.55% total cholesterol, 6.48% triglycerides, –1.98% A1c, –0.10% fasting glucose, and 45.06% homeostasis model of assessment - insulin resistance (HOMA-IR). The most common treatment-emergent adverse events (AEs) were grade 1 and included gynecomastia (36%), fatigue (34%), nipple pain (19%), and hot flush (18%). Five patients had serious AEs (none of which were deemed drug related).
Of 16 patients evaluable for objective response at week 25, 3 had a complete response and 5 achieved a partial response, resulting in an overall response rate of 50%.
“In contrast with castration, enzalutamide monotherapy was associated with stable bone mineral density and only modest changes in serum cholesterol and triglycerides,” noted Smith. “These results compare favorably with androgen deprivation therapy. “We believe the results of this phase II study support the further evaluation of enzalutamide as monotherapy in prostate cancer.”
All patients were followed for safety for 30 days following the last dose of enzalutamide. Patients who were felt to have clinical benefit at 25 weeks were eligible to continue treatment until progression or toxicity.
Commenting on the findings, Michael A. Carducci, MD, of the Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, observed that the design of the study “limits discussion of the durability of PSA declines and clinical benefits.” The short-term endpoints at 6 months “also limit what can be said long term as it relates to lipid profiles and fat body mass.” And he expressed concern about the “significant frequency of side effects,” albeit mostly grades 1 and 2, “in a population with only 40% with radiographic metastasis.” He acknowledged, however, that the study is ongoing and “there will be data that we will have in the future.”
Support for the study was provided by Astellas and Medivation.