ADDING ENZALUTAMIDE to androgen-deprivation therapy (ADT) significantly prolonged radiographic progression-free survival in men with metastatic hormone-sensitive prostate cancer, reducing the risk of progression or death by 61% compared with ADT plus placebo, according to results of the phase III trial known as “ARCHES.”

Adding enzalutamide to ADT also achieved significant benefits in clinically important subsets and in all secondary endpoints.

Andrew J. Armstrong, MD, MSc

“The radiographic progression-free survival benefit of the addition to enzalutamide to ADT is significant, but overall survival data are still immature. Enzalutamide and ADT were well tolerated in the study, with no unexpected side effects and a consistent safety profile. At the end of the study, all patients were offered enzalutamide so that they could get clinically beneficial treatment,” said lead author Andrew J. Armstrong, MD, MSc, Professor of Medicine at Duke University Cancer Center in Durham, North Carolina.

Dr. Armstrong presented an interim analysis of ARCHES at the 2019 Genitourinary Cancers Symposium.

“ADT is the mainstay of treatment for prostate cancer, but most men progress to castration-resistance within 1 to 3 years. Improved outcomes have been seen in metastatic castrate-resistant prostate cancer with docetaxel, abiraterone acetate, and radiotherapy to the prostate. These treatments have all been shown to delay progression of disease. [At the 2019 Genitourinary Cancers Symposium], we report our interim analysis of ARCHES, a phase III trial conducted  in the earlier disease setting [ie, before castration resistance develops],” Dr. Armstrong said.

Study Details

A TOTAL OF 1,150 MEN with metastatic hormone-sensitive prostate cancer were randomly assigned in a 1:1 ratio to receive enzalutamide at 160 mg/d plus ADT vs placebo plus ADT. The study was initiated in March 2016. Men were stratified according to low- and high-volume disease as well as by prior use  of docetaxel. All men had prior ADT for up to 3 months. Prior docetaxel for up to 6 months was also permitted for enrollment.

Criteria for discontinuation of treatment included radiographic disease progression, unacceptable toxicity, or the initiation of new therapy for prostate cancer.

At baseline, the median age was 70 years. About two-thirds of patients had a Gleason score of 8 or higher, and two-thirds had high-volume disease. About 45% had bone metastases only. About one-third had relapsed disease on local therapy. The median duration of prior ADT was 1.6 months.

Efficacy

AT A MEDIAN follow-up of 14.4 months, for the primary endpoint of radiographic progression-free survival, the enzalutamide-treated group had a significant 61% prolongation of time to radiographic progression or death. Median radiographic progression-free survival was not reached for enzalutamide at the interim analysis and was 19.45 months for placebo plus ADT.

An analysis of subgroups showed an improvement in radiographic progression-free survival in all subsets of patients treated with enzalutamide, including age, Gleason score, geographic region, disease pattern and spread, disease volume, and prior docetaxel.

“Importantly, nearly 20% of patients received prior docetaxel, and they all benefited from enzalutamide,” Dr. Armstrong said.

Enzalutamide improved secondary endpoints as well. Time to prostate-specific antigen (PSA) progression was significantly improved by 81% for enzalutamide vs placebo (P < .0001), and the rate of undetectable PSA was 68.1% for enzalutamide vs 17.6% for placebo (P < .0001).

The objective response rate was significantly better for enzalutamide: 83.1% vs 63.7%, respectively (P < .0001). The complete response rate (disappearance of all lesions on imaging) was 36.7% for enzalutamide vs 23.1% for placebo.

Time to initiation of next new antineoplastic therapy was significantly delayed by 72% with enzalutamide (P < .0001). The most common subsequent therapy was docetaxel, followed by abiraterone acetate.

An analysis of overall survival among patients enrolled in the ARCHES trial is still immature.

Quality of Life and Safety

QUALITY-OF-LIFE analyses are ongoing. According to baseline assessment by FACT-P, most men enrolled in the trial—including those with high-volume disease—were asymptomatic. Over time, most men in both arms maintained their quality of life. There was no difference in either arm for effect on urinary symptoms.

No unexpected adverse events were seen with enzalutamide. Similar treatment discontinuation rates were reported in both arms: 7.2% for enzalutamide and 5.2% for placebo.

The rates of adverse events of any grade were similar in both arms: 85.1% for enzalutamide vs 85.9% for placebo. The rate of grades 3 and 4 adverse events was around 25% in both arms.

Dr. Armstrong noted that more options for hormone-sensitive prostate cancer may be available by the end of 2019, including abiraterone acetate, docetaxel, enzalutamide, and possibly apalutamide. The choice of therapy will rest on patient-specific factors, payer factors, cost of treatment, and toxicities. ■ 

DISCLOSURE: Dr. Armstrong has received honoraria from Janssen Oncology, Sanofi, and Dendreon; is a consultant/advisor for Bayer, Sanofi, Novartis, Dendreon, Medivation, Janssen Biotech, and Pfizer; is on the speakers bureau for Dendreon, Sanofi, and Bayer; has received institutional research funding from Dendreon, Sanofi, Bayer, Pfizer, Novartis, Janssen Oncology, Medivation, Astellas Pharma, Gilead Sciences, Roche/Genentech, and Active Biotech; has an institutional patent/royalties/other intellectual property for circulating tumor cell novel capture technology; and has received travel/accommodations/ expenses from Dendreon, Medivation, Janssen Biotech, Sanofi, and Bayer.

REFERENCE

1. Armstrong A, Smulewitz RZ, Petrylak DP, et al: Phase 3 study of androgen deprivation therapy with enzalutamide or placebo in metastatic hormone-sensitive prostate cancer: The ARCHES trial. 2019 Genitourinary Cancers Symposium. Abstract 687. Presented February 14, 2019.