ASCO 2019: Overall Survival Results of a Phase III Randomized Trial of Standard-of-Care Therapy with or without Enzalutamide for Metastatic Hormone-Sensitive Prostate Cancer: ENZAMET, an ANZUP-led International Cooperative Group Trial

Chicago, IL ( Abiraterone and docetaxel are both standard of care options for available for patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the United States. CHAARTED demonstrated that docetaxel improved overall survival over ADT alone and after a median of 53.7 months, the median overall survival (OS) was 57.6 months in the chemohormonal arm and 47.2 months in the ADT alone arm.1 For patients with high volume disease, this difference was most pronounced, the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79).   No difference in OS was seen in the low volume cohort. For abiraterone, LATITUDE and STAMPEDE have provided ample evidence of a survival benefit over ADT alone. In LATITUDE, after a median follow-up of 30.4 months, the median OS with abiraterone was not reached vs. 34.7 months with ADT alone, hazard ratio (HR) for death = 0.62. STAMPEDE more recently demonstrated evidence of OS benefit for both high volume and low volume disease with data presented at ESMO 2018 (HR 0.64 p=0.034).2 However, neither of these studies compared the experimental arm with ADT + a nonsteroidal anti-androgen such as bicalutamide, nilutamide, or flutamide. Also, in the abiraterone studies, these patients were not docetaxel pre-treated. Enzalutamide (ENZA) has been shown to improve OS in men with CRPC, both before and after chemotherapy, and ARCHES showed that Enzalutamide improves rPFS in mHSPC over ADT alone. This abstract provides data on the use of enzalutamide, a potent androgen receptor (AR) inhibitor, versus a nonsteroidal anti-androgen (NSAA: bicalutamide, nilutamide, or flutamide) in addition to standard of care with or without docetaxel in mHSPC.
ASCO 2019 ENZAMET treatment

This abstract provides data on 1,125 patients who were randomly assigned to either ENZA or NSAA. The patient arms were well balanced and stratified disease volume based on CHAARTED criteria (Low volume = less than 4 bone metastases, high volume = 4 or more bone mets with one outside the spine/pelvis and or visceral metastases, age, comorbidities, planned early docetaxel, and study site. The primary end point was overall survival, and secondary endpoints included PSA progression and clinical progression-free survival, in addition to several correlative studies. Eligibility criteria are shown below.
ASCO 2019 ENZAMET Key eligibility

Baseline characteristics are shown below. Patients were well balanced by age, region, and performance status.
ASCO 2019 ENZAMET patient characteristics

Volume status was well matched as well. Early docetaxel occurred in 44-45% of all patients. The volume of metastases was similar in both arms and planned skeletal-related bone therapy was similar.
ASCO 2019 ENZAMET patient characteristics table 2

In terms of the primary endpoint, overall survival was significantly improved with enzalutamide over NSAA, with an HR of 0.67 (CI .52-.86, p=0.002), with 80% of patients alive at 3 years with enzalutamide and 72% with NSAA.
ASCO 2019 ENZAMET primary endpoint

Secondary endpoints showed that enzalutamide was superior for time to PSA rise, clinical progression or death (HR=0.39) and time to clinical progression (HR=0.40).
ASCO 2019 ENZAMET secondary endpoints

In terms of concurrent docetaxel, there was no difference in overall survival between the two arms. However, there was a benefit in clinical progression-free survival (HR=0.48).
ASCO 2019 ENZAMET concurrent docetaxel

In the following discussion by Tanya Dorff, MD, she notes that there are several significant factors (cost, length of treatment, toxicity, and volume status) to consider when choosing amongst the collection of agents now approved for mHSPC.
ASCO 2019 ENZAMET upfront agents

In terms of toxicity, the serious AE rate was similar between NSAA and enzalutamide. Notable differences included greater grade 2/3 fatigue, syncope, and seizures, all known side effects of enzalutamide and consistent with prior studies.
ASCO 2019 ENZAMET selected adverse events

When enzalutamide was added to docetaxel, certain adverse events (AEs) became more common than with docetaxel alone, including grade 2 sensory neuropathy, nail discoloration, grade 1/2 watery eyes, and grade 2 fatigue.
ASCO 2019 ENZAMET docetaxel adverse events
This is the first study to show a therapy with an overall survival benefit over NSAA in the mHSPC setting. This data, along with ARCHES, support the use of enzalutamide for mHSPC. Enzalutamide may not be appropriate in certain populations such as those with a seizure history, those with significant financial toxicity, and those with debilitating fatigue at baseline, but does appear to be safe and improve overall survival for the majority of patients with mHSPC. With respect to patients receiving docetaxel chemotherapy, while there is a significant improvement in progression-free survival, data at this time does not show improved overall survival with enzalutamide and there are increased toxicities – these risks and benefits should be carefully discussed with patients before embarking on a docetaxel/enzalutamide strategy in the mHSPC setting.

Following Dr. Sweeney’s presentation, ENZAMET was published in the New England Journal of Medicine 

Clinical trial information: NCT02446405

Presented By: Christopher Sweeney, MBBS, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

  1. Kyriakopoulos CE, Chen Y-H, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. Journal of Clinical Oncology 2018;36:1080.
  2. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. New England Journal of Medicine 2017;377:338-51.