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 disease progression or death by 61% compared with ADT plus placebo, according to the results of the phase III ARCHES trial.¹ Adding enzalutamide to ADT also achieved significant benefits in clinically important subsets and in all secondary endpoints.

The radiographic progression-free survival benefit of the addition of enzalutamide to ADT is significant, but overall survival data are still immature.

— Andrew J. Armstrong, MD

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“The radiographic progression-free survival benefit of the addition of 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, of Duke University Cancer Center, Durham, North Carolina.

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

“ADT is the mainstay of treatment for prostate cancer, but in most men, the disease progresses to castration resistance within 1 to 3 years. Improved outcomes have been seen in metastatic castration-resistant prostate cancer with docetaxel, abiraterone acetate, and radiotherapy to the prostate. These treatments have all been shown to delay progression of disease. We report the final analysis for the primary endpoint of radiographic progression-free survival in ARCHES, a phase III trial conducted in the earlier-disease setting [ie, before castration resistance develops],” Dr. Armstrong told listeners.

Study Details

The ARCHES trial randomly assigned 1,150 men with metastatic hormone-sensitive prostate cancer 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 received prior ADT for up to 3 months, and they could have had prior docetaxel for up to 6 months to still be eligible for enrollment.

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. Thus, most men had de novo metastatic hormone-sensitive prostate cancer with a high disease burden of metastases, but approximately a third of men had oligometastatic/low-volume disease.

Criteria for the discontinuation of treatment included radiographic disease progression, unacceptable toxicity, or the initiation of new therapy for prostate cancer. 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 disease progression or death. Median radiographic progression-free survival was not reached for enzalutamide at the interim analysis and was 19.5 months for placebo plus ADT. Overall survival at this time is immature with only 84 deaths and most men remaining on active therapy, but the hazard ratio of 0.81 favors enzalutamide. Nevertheless, the difference in overall survival between arms was not statistically significant at the time of the interim analysis, with plans for the final analysis planned after 342 deaths have occurred.

An analysis of subgroups showed 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. “Nearly 20% of patients had received prior docetaxel for metastatic hormone-sensitive prostate cancer, and these men had significant delays in radiographic progression-free survivel benefits 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 rate of complete response (disappearance of all lesions on imaging) was 36.7% for enzalutamide vs 23.1% for placebo. In addition, 68% vs 18% of men achieved an undetectable PSA over time with enzalutamide vs placebo.

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

Quality of Life and Safety

Quality-of-life analyses are ongoing. According to baseline assessment by the Functional Assessment of Cancer Therapy–Prostate questionnaire, 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. Notable enzalutamide-specific side effects of fatigue (24 vs 20%), hypertension (9 vs 6%), hot flushes (27 vs 22%), and fracture risk (6.5 vs 4.2%) were increased with enzalutamide, while seizures were rare (0.3% in each arm).

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

Dr. Armstrong noted that based on ARCHES and emerging data that will likely be forthcoming from TITAN and ENZAMET, men with metastatic hormone-sensitive prostate cancer will have more options for treatment soon, including abiraterone acetate, docetaxel, enzalutamide, and apalutamide, and some may have clear benefits from ADT and docetaxel plus a novel androgen receptor inhibitor. ARCHES represents the first study to show benefits from potent androgen receptor inhibition after docetaxel in this setting. The choice of therapy will rest on patient-specific factors such as disease volume and comorbidities, payer factors and cost of treatment, and toxicities. ■

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