ENZAMET Update confirms OS Benefit with Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer
Key Points:
- A follow-up of the phase 3 ENZAMET trial confirms the survival benefit with enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC).
- Exploratory analyses showed that enzalutamide is active in all prognostic subgroups.
- Investigators suggested that triplet therapy with testosterone suppression, enzalutamide, and docetaxel might best be used for patients with the poorest risk disease, particularly those with synchronous high-volume mHSPC.
In men with metastatic hormone-sensitive prostate cancer (mHSPC), the addition of enzalutamide to testosterone suppression continues to provide a significant improvement in overall survival (OS) after more than 5 years, according to an update from the phase 3 ENZAMET trial presented by Ian D. Davis, MBBS, PhD, FRACP, FAChPM, of Monash University and Eastern Health, in Australia, during the 2022 ASCO Annual Meeting (LBA5004).
After a median follow-up of 68 months, enzalutamide was associated with a 30% reduction in the risk of death compared with a standard nonsteroidal antiandrogen in patients with mHSPC receiving testosterone suppression (HR 0.70, 95% CI [0.58, 0.84]; P < .0001). The 5-year OS rate was 67% in the enzalutamide arm and 57% in the control group.
ENZAMET Data a Decade in the Making
ENZAMET (ANZUP 1304) is an open-label, randomized trial undertaken to evaluate whether enzalutamide would improve survival outcomes in patients with mHSPC. The study was planned about 10 years ago, when the survival benefit of enzalutamide in metastatic castration-resistant prostate cancer was established but before docetaxel had been demonstrated to improve OS in mHSPC.1,2
The trial enrolled 1,125 patients and included a mix of prognostic groups. Patients were randomly assigned to enzalutamide or a standard nonsteroidal antiandrogen, each with standard testosterone suppression. Concurrent docetaxel was allowed at the investigator's discretion. At the first planned interim analysis presented during the 2019 ASCO Annual Meeting Plenary Session, the trial met its primary endpoint, with enzalutamide demonstrating a significant 33% reduction in the risk of death over standard therapy (HR 0.67, 95% CI [0.52, 0.86]; P = .002).3
Prof. Ian D. Davis noted that this improvement reported in 2019 was observed despite the favorable outcomes in the control arm that used older antiandrogens and the option to use docetaxel at the investigator2019s discretion in either arm. He added that a health-related quality-of-life analysis after the interim OS analysis had shown some early additional toxicity with enzalutamide but that this was outweighed by the benefits of therapy. Although there was interest in whether triplet therapy with testosterone suppression, enzalutamide, and docetaxel would further enhance efficacy, the trial was not designed to answer this question. There appeared to be a progression-free survival benefit with triplet therapy, but this had not yet resulted in an OS benefit.
Second Analysis Confirms OS Advantage
Now 3 years since the interim analysis, the planned second analysis confirmed the OS advantage with enzalutamide in mHSPC, with an estimated median OS not reached in the enzalutamide group and 73.2 months for the control group (Figure). Upon experiencing progression on the study drug, 76% of patients in the control arm went on to receive enzalutamide or abiraterone, compared with 26% of those in the enzalutamide arm.
“This means that the survival benefits for enzalutamide were not due to lack of access to effective therapies in the control group, and also that the timing of treatment matters,” Prof. Ian D. Davis noted.
Abstract Discussant Russell Zelig Szmulewitz, MD, of the University of Chicago, echoed the importance of timing, noting that the OS advantage observed with enzalutamide despite three-quarters of patients on the control arm essentially crossing over and receiving enzalutamide or abiraterone/prednisone upon progression indicates that “there is still a robust survival advantage to the use of early enzalutamide in mHSPC.”
Exploratory subgroup analyses showed that enzalutamide was active in all prognostic groups tested, with a suggestion of a greater benefit in patients with a low tumor volume. The OS benefit with enzalutamide appeared to be smaller among patients who received early docetaxel at investigators' discretion; this may reflect higher-volume disease in docetaxel-treated patients, as 71% of those with high-volume disease received docetaxel compared with 37% of those with low-volume disease.
Prof. Ian D. Davis explained that weak androgen deprivation therapy was associated with the poorest outcomes regardless of prognostic group, whereas enzalutamide, docetaxel, or a combination of the 2 appeared to provide similar outcomes, even though patients receiving concurrent docetaxel likely had a poorer prognosis. He added that triplet therapy with testosterone suppression, enzalutamide, and docetaxel “can only be considered for patients able and willing to receive docetaxel. Our exploratory analyses raise the hypothesis that the greatest benefits of triplet therapy may be limited to those with the poorest prognosis disease, particularly those with synchronous and high-volume metastatic disease.”
Dr. Szmulewitz added that “the benefit of triplet therapy—enzalutamide on top of testosterone suppression and docetaxel—is clearest in the patient with de novo metastatic disease,” a finding that he suggested will impact practice.
"Dr. Russell Szmulewitz added that “the benefit of triplet therapy—enzalutamide on top of testosterone suppression and docetaxel—is clearest in the patient with de novo metastatic disease,” a finding that he suggested will impact practice."
Additional Follow-Up Planned
Looking ahead, the ENZAMET investigators are planning additional follow-up to assess outcomes in patients with long-lasting responses, as well as translational studies to identify potential predictors of response to various therapies, health economic analyses, and pooled analysis with other data sets to maximize the value and impact of the study.
— Mindy Tanzola, PhD
An earlier version of this article incorrectly stated the number of years since the interim analysis. It has been 3 years since the interim analysis. The article was updated on June 7, 2022.
Read original article here.
References
- Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-433.
- Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746.
- Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131.