Enzalutamide (Xtandi® Astellas Pharma and Pfizer), an androgen receptor signaling inhibitor, plus leuprolide (Eligard®; Tolmar Pharmaceuticals) significantly reduced the risk of metastasis or death by 58% versus placebo plus leuprolide (Hazard Ratio [HR]: 0.42; 95% Confidence Interval [CI], 0.30–0.61; P<0.0001), as assessed by the primary endpoint of metastasis-free survival (MFS), in men with non-metastatic hormone-sensitive prostate cancer (nmHSPC; also known as non-metastatic castration-sensitive prostate cancer or nmCSPC) with high-risk biochemical recurrence (BCR).
This conclusion is based on the outcome of the Phase 3 EMBARK trial, which evaluated patients across three study arms (enzalutamide plus leuprolide [n=355], placebo plus leuprolide [n=358], or enzalutamide monotherapy [n=355]), which was presented as a plenary session during the annual meeting of the American Urological Association (AUA), held April 28 – May 1, 2023 in Chicago, Ill, at the McCormick Place, Chicago, IL.
In this study, the overall safety profile was consistent with the known safety profile of each of the medicines. The most common adverse events in those treated with enzalutamide, which blocks the action of testosterone rather than lowering testosterone levels, plus leuprolide were fatigue, hot flush, and arthralgia and in those treated with enzalutamide monotherapy were fatigue, gynecomastia, and arthralgia.
The study was funded by Pfizer and Astellas Pharma, and the drug manufacturers are working toward securing Food and Drug Administration approval.
One of the deadliest cancers
“Despite advances in screening and treatment, prostate cancer remains one of the deadliest cancers,” noted Stephen J. Freedland, MD, Director of the Center for Integrated Research in Cancer and Lifestyle and the Warschaw Robertson Law Families Chair in Prostate Cancer at Cedars-Sinai Cancer and Co-Principal Investigator of the Clinical Trial. He is also the associate director for Training and Education at Cedars-Sinai Cancer.
Freedland is senior author of research that details new options for patients whose prostate cancer persists despite surgery and radiation therapy. The Phase 3 EMBARK clinical trial evaluated a drug that can boost effectiveness of the standard of care for recurrent prostate cancer-and works well on its own.
Standard of care
Standard of care for recurrent prostate cancer is androgen deprivation therapy (ADT), using medication to drastically reduce levels of the male hormone testosterone, which fuels prostate cancer growth. Freedland and colleagues tested therapeutic options to address two common issues associated with ADT.
The first is that ADT does not completely eliminate testosterone, leaving some of the hormone circulating and able to stimulate tumor growth. The other issue associated with ADT is that it has challenging side-effects including loss of sexual function.
“In this study, we identify practice-changing new treatment options and shed light on a group of patients who are not on the radar for most clinicians,” Freedland said.
“The EMBARK study is a Phase 3 trial exploring the potential of enzalutamide in patients with non-metastatic hormone-sensitive prostate cancer with high-risk BCR,” Freedland noted M.D.,
“If approved, we hope to bring a new option to men earlier in the course of their disease,” he said.
High-risk biochemical recurrence
“There are patients with localized prostate cancer who undergo prostatectomy or radiation therapy in an attempt to cure their disease, but, unfortunately, some patients will develop high-risk biochemical recurrence (BCR),” noted Neal Shore, M.D., F.A.C.S., U.S. Chief Medical Officer of Urology and Surgical Oncology, GenesisCare, Director, Carolina Urologic Research Center, and Primary Investigator for the EMBARK study.
“Importantly, some patients with high-risk biochemical recurrence (BCR) are at very high risk for developing metastatic disease, which can lead to a cascade of therapeutic interventions. The clinical goal of biochemical recurrence therapy is to delay cancer progression and avoid metastatic disease. The metastasis-free survival results from the EMBARK study demonstrate that this intervention with enzalutamide plus leuprolide was statistically significant for patients with high-risk biochemical recurrence,” Shore added.
In patients diagnosed with non-metastatic hormone-sensitive prostate cancer (nmHSPC; also known as non-metastatic castration-sensitive prostate cancer or nmCSPC (also known as non-metastatic castration-sensitive prostate cancer or nmCSPC) no evidence of the cancer spreading to distant parts of the body (metastases) was detectable with conventional radiological methods (CT/MRI), and the cancer still responds to medical or surgical treatment designed to lower testosterone levels. 
Of men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both, an estimated 20-40% will experience a biochemical recurrence (BCR) within 10 years.  About 9 out of 10 men with high-risk BCR will develop metastatic disease, and 1 in 3 will die as a result of the recurrence.
The EMBARK study*, which focused on men with high-risk BCR, enrolled 1,068 patients with nmHSPC with high-risk biochemical recurrence (BCR) from 244 sites in 17 countries.
In this study, participating patients were randomized to receive enzalutamide 160 mg daily plus leuprolide (n=355), enzalutamide 160 mg as a monotherapy (n=355), or placebo plus leuprolide (n=358). Leuprolide 22.5 mg was administered every 12 weeks.
Patients who were considered to experience high-risk BCR had a prostate-specific antigen doubling time (PSA-DT) ≤ 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 radiotherapy) as primary treatment for prostate cancer, or at least 2 ng/mL above the nadir if they had radiotherapy only as primary treatment for prostate cancer.
Consistent with the study’s primary endpoint, statistically significant and clinically meaningful improvements were also observed in the trial’s key secondary endpoints in both the enzalutamide combination and monotherapy arms.
Among patients receiving ADT plus enzalutamide, the risk of metastasis or death was reduced by 58% compared with ADT alone. And among patients receiving enzalutamide monotherapy the study results showed that treatment with enzalutamide reduced the risk of metastasis or death by 37% versus leuprolide plus placebo (HR: 0.63; 95% CI, 0.46–0.87; P=0.0049), meeting its metastasis-free survival endpoint.
Treatment with enzalutamide plus leuprolide and enzalutamide monotherapy reduced the risk of PSA progression by 93% (HR: 0.07; 95% CI, 0.03–0.14; P<0.0001) and 67% (HR: 0.33; 95% CI, 0.23–0.49; P<0.0001), respectively, versus placebo plus leuprolide.
The progression risk in starting a new antineoplastic therapy was reduced by 64% in those treated with enzalutamide plus leuprolide (HR: 0.36; 95% CI, 0.26–0.49; P<0.0001) and 46% in those treated with enzalutamide monotherapy (HR: 0.54; 95% CI, 0.41–0.71; P<0.0001) versus placebo plus leuprolide.
A positive trend in the key secondary endpoint of overall survival (OS) was also observed in the enzalutamide combination arm at the time of the analysis, but these data were not yet mature. Patients in the trial will be followed for a subsequent final OS analysis.
With both experimental options performing better than the standard of care, Freedland said some men might choose to add enzalutamide to their ADT treatment, while for others enzalutamide alone might be preferable.
“Some men might prefer enzalutamide alone as an option because it potentially allows them to avoid some of the side-effects associated with ADT, though further analysis of the trial data is needed to confirm that,” Freedland said. “The performance of enzalutamide, in combination with ADT and alone, is really impressive.”
This studies is an examples of the breadth of prostate cancer research undertaken by Cedars-Sinai Cancer physician-scientists, noted Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair.
“Too many men in the U.S. still die from prostate cancer each year,” Theodorescu said. “Our investigators are dedicated to developing next-generation treatments to best care for each and every patient.
“Our goal is for all patients to receive the most effective, personalized care in the timeliest fashion,” he concluded.
Note: * Per the EMBARK protocol, patients with nmHSPC and high-risk BCR are those initially treated by radical prostatectomy or radiotherapy, or both, with a prostate-specific antigen doubling time (PSA-DT) ≤ 9 months. High-risk BCR patients with a PSA-DT of ≤ 9 months have a higher risk of metastases and death.
Safety and Efficacy Study of Enzalutamide Plus Leuprolide in Patients With Nonmetastatic Prostate Cancer (EMBARK) – NCT02319837
Highlights of prescribing information
Enzalutamide (Xtandi® Astellas Pharma and Pfizer)[Prescribing Information]
Leuprolide (Eligard®; Tolmar Pharmaceuticals)[Prescribing Information]
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 American Society of Clinical Oncology. ASCO Answers: Prostate Cancer (2021). Online . Last accesses on April 28, 2023
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 Paller, Channing J et al. “Management of patients with biochemical recurrence after local therapy for prostate cancer.” Hematology/oncology clinics of North America vol. 27,6 (2013): 1205-19, viii. doi:10.1016/j.hoc.2013.08.005
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