Enzalutamide induces response in certain men with prostate cancer on active surveillance
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Enzalutamide monotherapy demonstrated significant treatment response among men on active surveillance for low- or intermediate-risk localized prostate cancer, according to phase 2 study results published in JAMA Oncology.
Additionally, researchers found enzalutamide (Xtandi; Astellas, Pfizer), an androgen receptor antagonist, to be well tolerated and a potential new treatment option for this patient population.
Rationale and methods
The effect of pharmacologic interventions that may delay prostate cancer progression in men undergoing active surveillance for low- or intermediate-risk prostate cancer is not well-known, according to study background.
For this reason, Neal D. Shore, MD, FACS, U.S. chief medical officer of surgery and oncology at GenesisCare USA and director of Carolina Urologic Research Center, and colleagues sought to compare the efficacy and safety of enzalutamide in combination with active surveillance vs. active surveillance alone among 227 men with low- or intermediate-risk prostate cancer receiving treatment across 66 U.S. and Canadian sites between June 2016 and August 2020.
The open-label, randomized ENACT study included 114 men (median age, 65 years; 92.1% white) assigned 160 mg enzalutamide plus active surveillance and 113 men (median age, 66 years; 87.6% white) assigned active surveillance alone. Researchers monitored the men for the first year of treatment and up to 2 years of follow-up.
Time to pathologic or therapeutic prostate cancer progression served as the primary endpoint. Incidence of a negative biopsy result, percentage of cancer-positive cores and incidence of secondary rise in serum PSA levels at 1 and 2 years, as well as time to PSA progression, served as secondary endpoints.
Key findings
Results showed enzalutamide reduced the risk for prostate cancer progression by 46% compared with active surveillance alone (HR = 0.54; 95% CI, 0.33-0.89) and delayed PSA progression by 6 months compared with active surveillance alone (HR = 0.71; 95% CI, 0.53-0.97).
Researchers additionally found that patients who received enzalutamide had 3.5-times higher odds of a negative biopsy result compared with those who received active surveillance alone.
Although researchers saw no significant difference between the two groups in serum PSA levels at 2 years, they did observe a significant reduction in the percentage of cancer-positive cores and the odds of a secondary rise in serum PSA levels at 1 year with enzalutamide.
Common adverse events reported with enzalutamide included fatigue in 55.4% and gynecomastia in 36.6%. Three deaths occurred in the enzalutamide group — none related to treatment.
Study limitations included potential confounding of the PSA progression analysis results due to effect of enzalutamide on PSA levels and the definition of PSA progression, which may have resulted in potential bias toward active surveillance. Moreover, the findings may not be generalizable to all racial and ethnic minority groups.
Implications
These findings suggest the potential of enzalutamide to offer an alternative short-term treatment option for men with low- or intermediate-risk prostate cancer on active surveillance, which could reduce the need for more aggressive treatment options, the researchers noted.
Despite the encouraging data, the trial fell short in specifically identifying men who could experience a clinical benefit from early systemic intervention with enzalutamide, according to an accompanying editorial by Susan Halabi, PhD, professor of biostatistics and bioinformatics at Duke University; Bradley C. Carthon, MD, PhD, interim director of the division of medical oncology and an associate professor at Emory University School of Medicine; and Wm. Kevin Kelly, DO, leader of the prostate cancer program and associate director of clinical research at Sidney Kimmel Cancer Center at Thomas Jefferson University.
“It is critical that patients with low-risk or intermediate-risk prostate cancer be followed for at least a decade with studies that are sufficiently powered to detect those differences in outcomes in various subsets of patients,” they wrote.
References:
- Halabi S, et al. JAMA Oncol. 2022;doi:10.1001/jamaoncol.2022.1623.
- Shore ND, et al. JAMA Oncol. 2022;doi:10.1001/jamaoncol.2022.1641.
Perspective
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Andres F. Correa, MD
Active surveillance for prostate cancer was introduced to reduce the impact of whole-gland prostate cancer treatment (radical prostatectomy and radiation) in men with localized prostate cancer. The treatment was first given to men with very low-risk prostate cancer and, over time, has been extended to those with low-risk and, recently, favorable intermediate disease. The push to pursue active surveillance has been the quality-of-life improvement with the treatment modality while providing a safe strategy for prostate cancer management.
The ENACT study assessed the impact of enzalutamide, a super androgen receptor blocker, in men with low- and favorable intermediate-risk prostate cancer being managed with active surveillance. The authors concluded that the addition of 1 year of enzalutamide for these men was safe and provided treatment response.
In my opinion, the study missed the mark completely, as it exposed a significant number of men to adverse events such as fatigue, gynecomastia and breast/nipple pain. Importantly, one of the main reasons to pursue active surveillance is to avoid sexual-related side effects, which occurred in almost 20% of the men in the treatment group. The study also failed to deliver meaningful or even actionable improvements in prostate cancer outcomes. First, the prostate cancer outcomes measured as part of the study (pathologic progression, therapeutic cancer progression and PSA progression) are outdated and, to a degree, self-fulfilling. Upgrading to low-volume grade group 2 is no longer a de facto reason to proceed to active treatment, and reduction of PSA is an expected treatment effect of the medication. Moreover, the impact of enzalutamide was only seen during the first year and mostly in men with low-risk disease.
In summary, the use of enzalutamide in this patient cohort mainly provided men in the treatment arm with adverse side effects, with very small — if any — deliverable benefit in regard to cancer control.
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