CHICAGO — Combining enzalutamide (Xtandi) with an androgen deprivation therapy (ADT) boosted metastasis-free survival (MFS) in patients with prostate cancer at high risk for biochemical recurrence, according to the EMBARK trial.

After a median follow up of 60.7 months, the combination of enzalutamide and leuprolide acetate ADT demonstrated a 58% reduction in the risk of a progression event compared with leuprolide acetate and placebo (HR 0.42, 95% CI 0.31-0.61, P<0.0001) in patients with nonmetastatic hormone-sensitive prostate cancer who had high-risk biochemical recurrence (BCR), reported Neal D. Shore, MD, of Carolina Urologic Research Center in Myrtle Beach, South Carolina.

Also in the phase III trial, the 3- and 5-year MFS rates were 92.9% and 87.3%, respectively, with the combination, compared with 83.5% and 71.4% with leuprolide acetate alone, he said during a plenary session at the American Urological Association annual meeting.

These results were consistent across subgroups, including those based on prostate-specific antigen (PSA) doubling time, baseline age, geographic region, baseline PSA, prior hormone therapy, and prior radical prostatectomy.

Interim overall survival (OS) data trended in favor of the enzalutamide-based combination (HR 0.59, 95% CI 0.38-0.90, P=0.0142), but Shore pointed out these results were not yet statistically significant.

He also reported that there were significant delays in time to PSA progression (HR 0.07, 95% CI 0.03-0.14, P<0.0001), and time to first new antineoplastic (HR 0.36, 95% CI 0.26-0.49, P<0.0001), with the combination.

“Enzalutamide in combination with ADT, if approved in this setting, has the potential to become new standard of care for patients with high-risk BCR,” said Shore. He referred to EMBARK’s results as “game-changing.”

EMBARK also evaluated enzalutamide monotherapy versus leuprolide acetate, with the enzalutamide arm statistically superior to the leuprolide arm (HR 0.63, 95% CI 0.46-0.87, P=0.0049) with regard to MFS, and also demonstrating a favorable OS trend.

As for safety, Shore reported that the most common adverse event (AE) leading to therapy discontinuation was fatigue (3.4% in the combination arm, 1.1% in the leuprolide acetate arm, and 2.3% in the enzalutamide arm). No AEs led to death in any of the arms.

The most common treatment-emergent AEs (TEAEs) were hot flash and fatigue in the combination and leuprolide acetate arms, and gynecomastia in the enzalutamide monotherapy arm (44.9%).

TEAEs of special interest occurring in more than 10% of patients in all three patient cohorts included musculoskeletal events, hypertension, fall, and fracture.

According to Shore, within 10 years of undergoing definitive therapy (i.e., prostatectomy or radiotherapy [RT]), 20%-50% of patients can experience BCR characterized by rising PSA levels.

“There’s limited level 1 evidence that tells us how best to treat these patients,” he pointed out, adding that these patients are at an increased risk of prostate-cancer specific mortality and progression of disease, as well as subjective worsening of their disease and painful metastases.

Thus, improved therapeutic options are needed, he said, noting that “we have evidence from phase III trials that demonstrate the value and clinical utility of treatment intensification with androgen receptor signalling inhibitors, such as enzalutamide.”

This randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,068 patients (mean age 69 or 70, depending on the cohort), with nonmetastatic hormone-sensitive prostate cancer at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region.

Patients with BCR were considered to be high risk if they had a PSA doubling time ≤9 months, serum testosterone ≥150 ng/dL (5.2 nmol/L), and screening PSA by the central laboratory ≥1 ng/mL if they had a radical prostatectomy (with or without RT) as primary treatment for prostate cancer, or at least 2 ng/mL above the nadir if they had RT only as primary treatment for prostate cancer.

These patients were randomized 1:1:1 to receive enzalutamide 160 mg daily plus leuprolide, enzalutamide 160 mg as a monotherapy, or placebo plus leuprolide.

Shore noted that at week 37 of treatment, if patients had PSA concentrations <0.2 ng/mL, then they underwent treatment deintensification, or a “holiday” from therapy.

“I think this is an important consideration given the importance of deintensification and side effect issues,” he said.

Patients restarted treatment if their levels rose to ≥2.0 ng/mL (if they had undergone radical prostatectomy), or ≥5.0 ng/mL without radical prostatectomy.

Shore and colleagues found that the proportion of patients in the combination, leuprolide acetate, and enzalutamide arms who had PSA <0.2 ng/mL at week 36 was 90.9%, 67.8%, and 85.9% respectively, with a median duration of treatment suspension of 20.2, 16.8, and 11.1 weeks among these patients.

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