CHICAGO — The oral androgen receptor inhibitor enzalutamide (Xtandi, Pfizer/Astellas) is an effective first-line treatment option for men with metastatic prostate cancer, conclude researchers reporting the phase 3 ENZAMET trial.
Enzalutamide significantly improved overall survival (OS) in comparison with a conventional nonsteroidal antiandrogen (NSAA) when both were added to standard of care (SOC) in this setting, reported lead author Christopher Sweeney, MD, of Dana Farber Cancer Institute, Boston, Massachusetts.
SOC was either a luteinizing hormone-releasing hormone analogue or surgical castration. Notably, the SOC also included early use of docetaxel (Taxotere, Pfizer) in about 45% of patients, which allowed investigators to also report on this "subgroup of interest." In total, the investigators randomly assigned 1125 men with metastatic prostate cancer to receive SOC plus either enzalutamide or a conventional NSAA (bicalutamide, nilutamide, or flutamide).
The overall survival rate at 3 years, which was the primary outcome, was 80% in the enzalutamide arm and 72% in the NSAA arm (hazard ratio [HR], 0.67; P = .002).
Criteria for early reporting were met at the first interim analysis after a median follow-up of 33 months. At that point, 64% of the enzalutamide arm were still receiving their assigned study treatment, in comparison with only 36% of the NSAA arm.
Enzalutamide also substantially improved time to progression compared to NSAA (P < .001).
The study was presented here at the plenary session (abstract LBA2) of the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting and were simultaneously published online in the New England Journal of Medicine.
At a meeting press conference, Sweeney summarized that enzalutamide plus SOC "represents an appropriate option for men with metastatic prostate cancer commencing testosterone suppression."
Complex Study Design
The results are big news, but Sweeney acknowledged that interpreting these early 3-year results is complex.
The complexity stems in part from the findings on prespecified subgroups of patients who did and those who did not also receive docetaxel as part of SOC in the study.
ENZAMET is the first metastatic hormone-sensitive prostate cancer trial to report OS data of an androgen receptor inhibitor (enzalutamide) and outcomes among a set of patients who also concurrently received docetaxel, explained Sweeney.
For the men whose SOC treatment included docetaxel (n = 503), there was no significant difference in OS between the enzalutamide arm and the NSAA arm at 3 years (HR, 0.90). "We do not see a significant treatment effect [of enzalutamide] in this early analysis," said Sweeney. "That's the first information that we as investigators will have to think through — what treatment to give our patients if they've had docetaxel," he added.
In other words, if there is no survival benefit with enzalutamide for patients who also receive docetaxel, then perhaps enazulatmide, being a more expensive therapy, can be withheld at this early point, because docetaxel can do the job instead, especially in select patients, he suggested.
Enzalutamide is priced in the neighborhood of $10,000 per month, said Sweeney, whereas chemotherapy is much less costly.
However, this clinical scenario needs an asterisk. Most of the men in the docetaxel subgroup (71%) had high-volume, poor-prognosis metastatic disease (four or more visceral metastases).
On the other hand, for the men whose SOC treatment did not include docetaxel (n = 622), there was indeed a notable difference in OS between the enzalutamide arm and the NSAA arm at 3 years (HR, 0.53). Only about a third (37%) of these men had high-volume disease. In other words, enzalutamide was effective in improving survival when not competing with docetaxel and in patients with mostly low-volume disease.
Serious adverse events (AEs) within 30 days of study treatment occurred among 42% of men in the enzalutamide arm and 34% in the NSAA arm, which was "commensurate with the different durations of study treatment," the study authors report in their meeting abstract.
However, in terms of AEs, Sweeney pointed out that in comparison to the NSAA arm, the enzalutamide arm had higher rates of grade 2 and 3 hypertension, fatigue, falls, and syncope, as well as seizures (any grade). "We as physicians have to say, 'Are the patients fit enough even for the hormone enzalutamide?' " said Sweeney, adding that clinicians need to counsel patients about risk.
He also highlighted the fact that the rate of treatment discontinuations due to drug-related adverse events was 16% in the enzalutamide arm vs 4% in the NSAA arm. Also, seven patients (1%) in the enzalutamide group experienced seizures, vs no patients in the NSAA group.
What to Use as Initial Treatment?
Currently, in the United States, enzalutamide is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. It is also indicated for the treatment of men with earlier, nonmetastatic, castration-resistant prostate cancer.
Enzalutamide will now also be used in this new setting of metastatic hormone-sensitive prostate cancer, predicted Charles Drake, MD, PhD, director of genitourinary oncology, New York–Presbyterian/Columbia University Medical Center, and associate director for clinical research, Herbert Irving Comprehensive Cancer Center, New York City, who was not involved in the new study.
"I think this will be a regimen that people use in the first line," he said told Medscape Medical News.
There are currently two established treatment options in the first line, he noted.
Men with metastatic hormone-sensitive prostate cancer experience a survival benefit with the addition of either docetaxel chemotherapy or abiraterone acetate (Zytiga, Janssen) to androgen deprivation therapy; both approaches are current standards of care and are supported by evidence from the major clinical trials, said Drake, who was asked for comment.
Patients with metastatic hormone-sensitive prostate cancer and their clinicians in this first-line setting now have more choice, he said. But the current trial is only a partial help.
"These sorts of trials [such as ENZAMET] are not perhaps as helpful for patients to make a decision [among all current choices], but they are designed to show, for example, that enzalutamide is associated with a better long-term survival as opposed to the old standard of care," Drake told Medscape Medical News.
In hypothetical head-to-head trials, Drake suspects that the current choices would be very similar in efficacy: "I doubt that abiraterone would beat chemo, or chemo would beat abiraterone. I doubt that enzalutamide would beat chemo or abiraterone."
Sweeney had similar thoughts, calling the potential competition between the rival agents a likely case of "Pepsi vs Coke."
"There is no evidence that one is better than the other," said Tanya Dorff, MD, of City of Hope Cancer Center, Duarte, California, who acted as discussant at the meeting. Additionally, no studies have suggested synergy when the agents are used in combination, she said.
Dorff pointed out that some characteristics make one agent more attractive than the other. For example, chemotherapy is a short-term treatment, whereas the antiandrogens are everyday, long-term treatments.
Enzalutamide has the advantage of not requiring steroids (like arbiraterone) but has the disadvantage of causing fatigue, among other adverse events, she added. Docetaxel is associated with peripheral neuropathy and other side effects.
Abiraterone use is not advisable for patients who are at risk for diabetes and cardiovascular disease, she said.
The new study was a collaboration between the University of Sydney; the Australian and New Zealand Urogenital and Prostate Cancer Trials Group; the National Health and Medical Research Council, Australia; Cancer Trials Ireland; and the NCIC Clinical Trials Group.
Exclusion criteria included prior cytotoxic chemotherapy for prostate cancer, other than docetaxel.
Sweeney explained that ENZAMET randomization was stratified by a number of variables, including the aforementioned early docetaxel vs no docetaxel. Another variable was volume of disease: high volume (four or more visceral metastases) vs low volume. The authors performed related subgroup analyses to assess possible modulation of the treatment effect.
Table. Select Subgroup Analyses
|Group (n)||HR (95% CI)||NSAA 3-Yr OS||ENZA 3-Yr OS|
|High-volume disease (596)||0.74 (0.55 – 1.01)||64%||71%|
|Low-volume disease (529)||0.48 (0.28 – 0.80)||82%||90%|
|No planned early DOC (622)||0.53 (0.36 – 0.73)||70%||83%|
|Planned early DOC (503)||0.90 (0.62 – 1.35)||75%||74%|
The study investigators received funding from Astellas, makers of enzalutamide, for conduct of this investigator-sponsored trial. Sweeney has served in a consulting or advisory role to Astellas as well as other pharmaceutical companies and has received research funding from Astellas and other companies. Drake has served as a paid consultant to Janssen, the makers of apalutamide, and to Bayer, the makers of daralutamide. Dorff has served as a consultant to Astellas and has financial ties to other pharmaceutical companies.
American Society of Clinical Oncology (ASCO) 2019 Annual Meeting: Abstract LBA2. Presented June 2, 2019.
N Eng J Med. Published online June 2, 2019. Abstract
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Cite this: Enzalutamide Joins Initial Tx List for Metastatic Prostate Cancer - Medscape - Jun 03, 2019.