ASCO GU 2019: Phase 3 Study of Androgen Deprivation Therapy with Enzalutamide or Placebo in Metastatic Hormone-Sensitive Prostate Cancer: The ARCHES Trial

San Francisco, CA ( Enzalutamide (ENZA) is an androgen receptor signaling inhibitor which inhibits the androgen receptor signaling pathway by blocking the binding of androgen to the androgen receptor as well as inhibition of nuclear translocation of the androgen receptor.1 Enzalutamide has been shown to be effective in improving overall survival in patients with metastatic castration resistant prostate cancer (mCRPC) both before and after chemotherapy.2,3

First in 2012, AFFIRM showed in a population of post-chemotherapy mCRPC patients that enzalutamide improved overall survival compared with placebo (18.4 months vs 13.6 months, HR 0.63, p<0.001), which led to its first FDA approval in prostate cancer.2 Next in 2014, PREVAIL showed that enzalutamide was able to decrease the risk of radiographic progression and death and delay chemotherapy which broadened its FDA approval to all patients with mCRPC.3 Most recently, based on the results of PROSPER which showed that enzalutamide significantly reduced the risk of developing M1 CRPC by prolonging metastasis-free survival (36.6 vs 14.7 months), enzalutamide gained an FDA indication in 2018 for use in men with non-metastatic CRPC with a PSA doubling time of less than 10 months.This study aims to provide evidence for the only space left untouched by enzalutamide – metastatic castration sensitive prostate cancer.

ASCO GU 2019 ARCHES Study Design

This was a phase III, international double-blind clinical trial which randomized patients to enzalutamide 160 mg/day plus androgen deprivation therapy (ADT) or placebo (PBO) plus ADT. Patients were stratified by disease volume based on CHAARTED criteria as well as prior docetaxel therapy (high volume = presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis). The primary endpoint of the study was radiographic progression-free survival (PFS) or death within 24 weeks of stopping treatment.

A total of 1150 men were randomized to enzalutamide or placebo. Baseline characteristics were well balanced between the two cohorts.

ASCO GU 2019 Baseline Patient Characteristics

The majority of patients (63%) had metastatic prostate cancer at initial diagnosis. Most patients (63%) also had high volume disease. 18% of patients had prior docetaxel chemotherapy.

At a median follow up of 14.4 months, combination enzalutamide plus ADT significantly improved radiographic progression-free survival in all pre-specified subgroups of disease including patients who had received prior docetaxel chemotherapy.

ASCO GU 2019 Primary Endpoint rPFS

68.1% of patients on enzalutamide were able to reach a PSA <0.2, compared to 17.6% of patients on placebo. The objective response rate was 83.3% for enzalutamide arm and 17.6% for placebo + ADT arm.

In terms of safety, grade 3/4 adverse events were similar between the enzalutamide group and placebo patients (23.6% vs 24.7%). The most frequent adverse events (AEs) were hot flashes, fatigue, and arthralgia, which were all present >10% in both the placebo arm and enzalutamide arm (as both arms include ADT). Quality of life was not significantly different between the two arms, as defined by FACT-P (The Functional Assessment of Cancer Therapy-Prostate).

ASCO GU 2019 Adverse Events

ASCO GU 2019 Subgroup Analysis of rPFS

Enzalutamide significantly increases radiographic progression-free survival for patients with metastatic castration sensitive prostate cancer. Importantly, subgroup analysis shows that this improvement in rPFS holds in both high and low volume patients, as well as for patients who have had prior docetaxel chemotherapy. Analysis of overall survival is immature at this time due to a very low number of deaths in both arms. Enzalutamide was well tolerated and did not decrease the quality of life. Based on this preliminary data, I suspect enzalutamide will eventually be added to the growing armamentarium of therapies (abiraterone, docetaxel) for patients with mCSPC. Future studies should help answer sequencing questions as well as how to choose the best initial therapy.

Clinical Trial Information: NCT02677896

Presented by: Andrew J. Armstrong, MD, Professor of Medicine, Associate Professor in Pharmacology and Cancer Biology, Associate Professor in Surgery, Duke University School of Medicine, Durham, NC 

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

  1. Zhang T, Zhu J, George DJ, Armstrong AJ. Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer. Expert opinion on pharmacotherapy 2015;16:473-85.
  2. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine 2012;367:1187-97.
  3. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. The New England journal of medicine 2014;371:424-33.
  4. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). American Society of Clinical Oncology; 2018.