Enzalutamide Ups Mets-free Survival, QoL in Prostate Cancer

Adding enzalutamide (Xtandi) to androgen deprivation therapy (ADT) can extend metastasis-free survival while maintaining quality of life in men with prostate cancer who have a high-risk for biochemical recurrence, according to new research presented at the European Society of Medical Oncology (ESMO) meeting in Madrid.

At 5 years, nearly 90% of patients receiving enzalutamide plus the ADT leuprolide (multiple brands) were metastasis-free, while 80% of those receiving only enzalutamide and about 71% of those receiving only leuprolide were metastasis-free.

In a related analysis of patient-reported outcomes, investigators found that patients who received enzalutamide did not appear to have worse quality of life compared with those treated with leuprolide alone.

“This could be a game-changer for one of the most common disease states in prostate cancer,” lead author Stephen Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Cancer in Los Angeles, told Medscape Medical News. The study was published online October 19 in the New England Journal of Medicine.

The results “confirm that in this population, as in men with more advanced stages, adding an androgen-receptor inhibitor [enzalutamide] increases the efficacy of androgen deprivation therapy,” Ana Aparicio, MD, from University of Texas MD Anderson Cancer Center in Houston, wrote in an accompanying editorial.

Standard care in this patient population relies on ADT to suppress testosterone, which would otherwise stimulate cancer cell growth. However, Freedland explained, “when you go on androgen deprivation therapy, the testosterone level in the blood is reduced, but not completely eliminated. The concern is that the testosterone that remains may still be enough to stimulate tumor growth.”

Enzalutamide, an oral androgen receptor inhibitor, has already shown benefits in patients with metastases, and the current EMBARK trial explored whether the inhibitor can help men with earlier-stage disease who are at risk for metastases.

The findings from the phase 3 EMBARK trial, also published in NEJM Evidence, included 1068 patients with prostate cancer at high-risk for biochemical recurrence. Patients, who had a median age of 69 years, spanned 244 sites across 17 countries.

Patients had a median prostate-specific antigen (PSA) doubling time of 4.9 months, with a median PSA of 5.2 ng/mL. Those with PSA doubling times of 9 months or less are considered at high-risk for biochemical recurrence and increased risk for death from prostate cancer.

Freedland and colleagues randomly assigned patients to three groups — enzalutamide 160 mg plus leuprolide every 12 weeks (n = 355), enzalutamide monotherapy (n = 355), and placebo plus leuprolide (n = 358). Patients received treatment for 38.7 months, on average. 

At 5-years, 87.3% of men in the combination group were metastasis-free compared with 80% in the monotherapy group and 71.4% in the leuprolide-only group. Compared with leuprolide alone, combining enzalutamide and leuprolide reduced the risk for metastasis or death by 58% (hazard ratio [HR], 0.42; P < .001). And compared with enzalutamide monotherapy, the combination also significantly reduced the risk for metastasis or death compared with leuprolide alone (HR, 0.63; P = .005).

The estimated proportion of patients free from PSA progression at 5 years was 97.4% in the combination group, 88.9% in the monotherapy group, and 70% in the leuprolide-only group.

At the time of data cutoff, 33 (9%) patients in the combination group, 42 (12%) in the monotherapy group, and 55 (15%) in the leuprolide-only group had died.

Nearly all (97%) patients experienced adverse events, most of which (86.4%) were treatment-related. Overall, 46.5% of patients in the combination group experienced a grade 3 or higher adverse event compared with 50% in the enzalutamide monotherapy group and 42.7% in the leuprolide-only group. Clustered adverse effects occurred in 80% or more patients in all three groups, with the most common cluster combining fatigue, falls, fractures, hypertension, and musculoskeletal events.

The most common adverse events in the enzalutamide monotherapy group, occurring in at least 30% of patients, included gynecomastia, joint pain, hot flashes, and fatigue. Nipple pain and breast tenderness were also common side effects in the enzalutamide monotherapy arm — occurring in 15.3% and 14.4% of patients, respectively — compared with the combination (3.1% and 1.1%) or leuprolide-only (1.1% and 1.1%) groups.

However, Freedland explained, “our quality-of-life data show that you don’t need to sacrifice global quality of life to get these cancer benefits.”

Patient-reported outcomes from EMBARK revealed that both enzalutamide combination and monotherapy vs leuprolide alone preserved high health-related quality of life in patients with a high-risk for biochemical recurrence.

More specifically, Freedland and colleagues found no differences in the time to first clinically meaningful deterioration based on questionnaires that rated pain and functional status. Functional status measures included physical, social, and emotional well-being as well as symptom severity.

However, some differences emerged. For instance, time to confirmed clinically meaningful deterioration in physical well-being score was significantly shorter among patients receiving enzalutamide compared with leuprolide monotherapy — 24.8 months in the combination group and 27.6 months in the enzalutamide-only group vs 49.8 months in the leuprolide-only group (HR, 1.41 and 1.35, respectively).

However, sexual activity appeared to be better preserved among patients receiving enzalutamide monotherapy compared with leuprolide alone. The median time to confirmed clinically meaningful deterioration in sexual activity score was 5.6 months with enzalutamide monotherapy vs 3 months for leuprolide alone (HR, 0.76).

Given the slightly different side-effect profiles in the enzalutamide combination and monotherapy groups, Freedland noted that “it will be up to patients and care providers to decide which is the right choice for them. I think the important message is that both are a major step forward from the current standard of care, which is androgen deprivation therapy alone.”

Pedro Barata, MD, who was not involved in the research, also noted that “this is the first time we have seen this kind of results with a novel hormonal therapy without castration.”

Overall, “the findings of this trial confirm the benefit of adding a novel hormonal therapy such as enzalutamide earlier in the course of this disease,” said Barata, a medical oncologist and director of the Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, Cleveland, Ohio.

However, he explained that many patients with “rising PSA and short doubling time are known to have metastatic disease as detected by PSMA PET and are already being offered a novel hormonal therapy combined with castration. Perhaps it will be an opportunity for men who don’t want to be castrated to be offered an anti–androgen-like enzalutamide by itself without castration in this patient population.”

Research was funded by Pfizer and Astellas Pharma, manufacturers of enzalutamide.

ESMO Congress 2023: Abstract 1766MO. Presented October 22, 2023.

New Engl J Med. Published online October 19, 2023. Abstract, Editorial

NEJM Evidence. Published online October 21, 2023. Full text

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Howard Wolinsky is a Chicago-based medical freelancer and a patient diagnosed with low-risk prostate cancer who has been on active surveillance since 2010.

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