Enzalutamide Improves Survival in Hormone-Sensitive Prostate Cancer

The treatment of metastatic hormone-sensitive prostate cancer (HSPC) has undergone a major evolution in recent years. While androgen deprivation therapy (ADT) remains the backbone of care, several studies have demonstrated an improvement in long-term survival when the cytotoxic agent docetaxel or the androgen biosynthesis inhibitor abiraterone are added to ADT. Enzalutamide is a potent direct androgen receptor inhibitor that demonstrated improved overall survival (OS) in patients with castration-resistant prostate cancer (CRPC), and prolonged radiologic progression-free survival (rPFS) in metastatic HSPC in the recently reported phase III ARCHES trial. Apalutamide, another direct androgen inhibitor which was compared to placebo in the TITAN trial that was presented at the oral genitourinary session of American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 5006), demonstrated improved rPFS and also survival benefit, regardless of prior docetaxel use. In addition, the interin results from a phase III ENZAMET (Abstract LBA2) of enzalutamide plus ADT plus a standard of care trial antiandrogen (NSAA) in patients with metastatic HSPC were presented at the plenary session by Christopher Sweeney, MBBS (Dana-Farber Cancer Institute, Boston, Massachusetts, United States). Among 1,125 patients included in the trial, 503 received concurrent docetaxel and 602 did not.

At a median follow-up of 34 months, the study had met its primary endpoint of improved OS with the addition of enzalutamide to ADT compared to ADT plus NSAA (HR 0.67, P = .002). At 36 months, 80% of patients receiving enzalutamide plus ADT were alive, compared to 72% of patients receiving ADT plus NSAA. Treatment with enzalutamide also resulted in prolonged time to prostate-specific antigen (PSA) rise, clinical progression, or death (HR 0.39, P<.001) and time to clinical progression (HR 0.40, P<.001). In the cohort of 503 patients who were receiving concurrent treatment with docetaxel during this study, enzalutamide plus ADT resulted in an improved clinical PFS compared to ADT plus NSAA (HR 0.48), but there was no improvement in OS (HR 0.90).

Serious adverse events (AEs) occurred more frequently in patients receiving enzalutamide (42% vs 34%), and more patients receiving enzalutamide discontinued due to AEs. Fatigue, syncope, and hypertension were among the most common grade 3 AEs, occurring more frequently in the enzalutamide group than in the NSAA group. In addition, seizures of any grade (a known AE of enzulatamide) occurred in 7 patients. Among patients receiving docetaxel, AEs associated with docetaxel occurred more frequently in patients who received enzalutamide compared to those who received NSAA.

Dr Sweeney concluded that the addition of enzalutamide to ADT improves time to progression and OS, supporting enzalutamide as an appropriate treatment option for patients with both low- and high-volume metastatic HSPC. He noted that for patients who are candidates for docetaxel when starting ADT, quality-of-life analyses and longer follow-up are needed to determine whether the delay in progression with concurrent enzalutamide is clinically meaningful and augments survival beyond 3 years. How best to select between available treatments in the HSPC setting is now a major question. In her discussion of this abstract, Tanya Dorff, MD (City of Hope, Los Angeles, California, United States), noted that several factors, including cost, length of treatment, toxicity, and tumor volume, will likely influence selection between available agents. However, she believes that at this time there is no strong evidence for using combination of docetaxel and enzalutamide in these patients.

Results from both ENZAMET and TITAN trials were simultaneously published in The New England Journal of Medicine.

J Clin Oncol. 2019;37(suppl 18): LBA2.

N Engl J Med. 2019 June 2. [Epub ahead of print.]
enzalutamide-plus-ADT-for-HSPC

Clinical Opinion Poll

How would you treat 39 y/o pt with metastatic HR-/HER2+ breast ca (liver & multiple CNS mets) who has PD in CNS (6m after WBRT while on THP regimen)?