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Enzalutamide, ADT combination improves radiographic PFS in metastatic prostate cancer
SAN FRANCISCO — The addition of enzalutamide to androgen deprivation therapy significantly improved radiographic PFS among men with metastatic hormone-sensitive prostate cancer, according to data from the multinational, double-blind, phase 3 ARCHES trial presented at Genitourinary Cancers Symposium.
The androgen receptor inhibitor enzalutamide (Xtandi; Astellas, Pfizer Oncology) has demonstrated benefit among men with metastatic and nonmetastatic castration-resistant prostate cancer, but its efficacy in hormone-sensitive prostate cancer had been unknown.
“Men who present with metastatic prostate cancer have a poor prognosis despite hormonal therapy,” Andrew J. Armstrong, MD, professor of medicine and associate professor in pharmacology and cancer biology in the department of medicine at Duke University School of Medicine, and member of the Duke Cancer Institute, told HemOnc Today. “ARCHES enrolled men with metastatic hormone-sensitive prostate cancer, and permitted patients who had previously completed docetaxel chemotherapy.
“Currently, no other trials have been reported that evaluate the sequential of docetaxel followed by potent androgen receptor inhibition with ADT,” he added. “In addition, enzalutamide alone with ADT may provide significant benefits in men with metastatic hormone-sensitive prostate cancer, similar to what has been observed in the castration-resistant setting.”
Researchers randomly assigned 1,150 men to 160 mg daily enzalutamide (n = 574) or placebo (n = 576) with ADT. Sixty-seven percent of the men had distant metastasis at initial diagnosis, 63% had high-volume disease and 18% had previously received docetaxel.
Radiographic PFS assessed centrally or death within 24 weeks of treatment discontinuation served as the study’s primary endpoint. Secondary endpoints included time to PSA progression, PSA and radiographic responses, and OS.
Median follow-up was 14.4 months.
Median radiographic PFS was not reached in the enzalutamide group and was 19.4 months in the placebo group, indicating a significant improvement with enzalutamide (HR = 0.39; 95% CI, 0.3-0.5).
Researchers reported similar improvement in radiographic PFS across patient subgroups of disease volume, pattern of spread, region and prior docetaxel, with HRs ranging from 0.24 to 0.53.
Time to PSA progression (HR = 0.19; 95% CI, 0.13-0.26) and time to initiation of new antineoplastic therapy (HR = 0.28; 95% CI, 0.2-0.4) also significantly improved with enzalutamide.
More men in the enzalutamide group achieved undetectable PSA levels (68.1% vs. 17.6%) and objective response (83.1% vs. 63.7%; P < .0001 for both).
OS data were immature at the time of the analysis.
“Currently, no data exist supporting the benefits of sequential use of docetaxel/ADT with a second-generation androgen receptor pathway inhibitor,” Armstrong told HemOnc Today. “ARCHES provides evidence for such an approach, particularly in men with high-volume, metastatic hormone-sensitive prostate cancer who are typically offered docetaxel chemotherapy with ADT as initial therapy.
“In addition, ARCHES provides evidence of the clinical benefits of enzalutamide in the broader population of men with metastatic hormone-sensitive prostate cancer regardless of age, pattern of spread, disease burden or prior chemotherapy use, and offers an alternative therapy to abiraterone acetate with prednisone and ADT for these men,” he added.
Grade 3 to grade 4 adverse events occurred among 23.6% of men in the enzalutamide group compared with 24.7% of the placebo group. Researchers reported no new safety signals.
The ongoing ENZAMET study is evaluating concurrent enzalutamide with ADT vs. ADT alone in this patient population, with enzalutamide started with docetaxel and ADT instead of sequentially, Armstrong said.
“This study’s primary endpoint is OS, and it is anticipated to add to the evidence supporting enzalutamide in this metastatic hormone-sensitive prostate cancer setting,” he said. “Likely within the next year, men with metastatic hormone-sensitive prostate cancer will be faced with a range of choices, including abiraterone, enzalutamide, apalutamide [Erleada, Janssen Oncology] and docetaxel, and emerging evidence is suggesting that for high-volume men, chemohormonal therapy with ADT/docetaxel and enzalutamide may be a reasonable approach, whereas for low-volume men, ADT with potent androgen receptor inhibition is reasonable, with decisions on which androgen receptor inhibitor to use based on individualized factors, such as contraindications to prednisone, comorbidity/age and costs.”
Efforts to study additional systemic agents, including PARP inhibitors, immunotherapy and other combination approaches, in this setting are warranted to improve upon these outcomes, Armstrong said. – by Alexandra Todak
Reference:
Armstrong AJ, et al. Abstract 687. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.
Disclosures: Astellas and Medivation funded this study. Armstrong reports honoraria from Dendreon, Janssen Oncology and Sanofi; consultant/advisory or speakers bureau roles with Astellas, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Janssen Biotech, Medivation, Pfizer and Sanofi; research funding to his institution from Active Biotech, Astellas Pharma, Bayer, Bristol-Myers Squibb, Dendreon, Gilead Sciences, Janssen Oncology, Medivation, Novartis, Pfizer, Roche/Genentech and Sanofi; travel accommodations or expenses from Astellas, Bayer, Dendreon and Janssen; and patents or royalties on circulating tumor cell novel capture technology. The other authors report no relevant financial disclosures.