Enzalutamide Improves Undetectable PSA Rates Alone and With Leuprolide in Nonmetastatic CSPC


Enzalutamide alone and with leuprolide led to greater rates of undetectable PSA levels vs leuprolide alone in castration-sensitive prostate cancer.

Stephen J. Freedland, MD

Stephen J. Freedland, MD

Treatment with enzalutamide (Xtandi), both in combination with leuprolide and as monotherapy, led to a greater of number patients with undetectable prostate-specific antigen (PSA) levels vs leuprolide alone among patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC) with high risk of biochemical recurrence (BCR), according to findings from a post-hoc analysis of the phase 3 EMBARK trial (NCT02319837) presented during the 2024 American Urological Association Annual Meeting.1

At the January 31, 2023, data cutoff, patients in the combination arm (n = 355) and the enzalutamide monotherapy arm (n = 355) achieved undetectable PSA (< 0.2 ng/mL) at week 25 or sooner at rates of 89% and 82%, respectively, compared with 63% among patients who received leuprolide monotherapy (n = 358). Moreover, patients in the combination (n = 241), enzalutamide monotherapy (n = 270), and leuprolide monotherapy arms (n = 203) who reinitiated treatment after week 37 achieved undetectable PSA rates of 96%, 90%, and 73%, respectively.

Additionally, investigators emphasized that undetectable PSA was associated with superior metastasis-free survival (MFS) regardless of which treatment patients received. Patients who reinitiated treatment and achieved undetectable PSA levels in the combination (n = 231), enzalutamide monotherapy (n = 242), and leuprolide monotherapy arms (n = 149) achieved a median MFS by blinded independent central review (BICR) of not reached (NR; 95% CI, NR-NR), NR (95% CI, NR-NR), and NR (95% CI, 80.1%-NR), respectively. Comparatively, patients in the combination (n = 10), enzalutamide monotherapy (n = 28), and leuprolide monotherapy arms (n = 54) who resumed treatment but did not achieve undetectable PSA levels achieved a median MFS of 50.5 months (95% CI, 29.1-NR), 42.4 months (95% CI, 27.5-NR), and 55.3 months (95% CI, 44.2-NR), respectively.

“A key feature of EMBARK was that patients were treated for 36 weeks, followed by treatment suspension at week 37 if PSA levels at week 36 were undetectable and re-initiation if PSA levels rose to protocol-defined thresholds,” Stephen J. Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle as well as the associate director for Training and Education at the Samuel Oschin Comprehensive Cancer Institute at Cedars Sinai in Los Angeles, California, explained during the presentation. “[This] post-hoc analysis of PSA dynamics in the EMBARK trial [aims] to understand the time course to undetectable PSA and the likelihood of undetectable PSA levels after treatment re-initiation.”

Enzalutamide monotherapy was approved by the FDA for the treatment of patients with nonmetastatic CSPC with high-risk BCR in November 2023. The regulatory decision was supported by findings from EMBARK.2

EMBARK enrolled patients with nonmetastatic CSPC with a PSA doubling time of 9 months or less, no metastases on bone scan or CT/MRI, testosterone of 150 ng/dL or greater, no prior hormonal therapy at least 9 months prior to randomization, and a screening PSA level of at least 1 ng/mL after radical prostatectomy and at least 2 ng/mL above the nadir for those who received external beam radiotherapy. Patients were stratified by screening PSA level (≤ 10 ng/mL vs > 10 ng/mL), PSA doubling time (≤ 3 months vs > 3 months vs ≤ 9 months), and prior hormonal therapy (yes vs no).1

Patients were randomly assigned 1:1:1 to receive oral enzalutamide 160 daily plus intramuscular leuprolide 22.5 mg every 12 weeks, enzalutamide monotherapy at the same dosing schedule, or leuprolide monotherapy at the same dosing schedule. At week 36, patients in all arms with a PSA of less than 0.2 ng/mL suspended treatment at week 37, were monitored, and reinitiated treatment if their PSA rose. Those who did not achieve this PSA threshold remained on treatment.

The primary end point was MFS by BICR for the enzalutamide combination vs leuprolide monotherapy. Key secondary end points included MFS for enzalutamide monotherapy vs leuprolide, time to PSA progression, time to first use of new antineoplastic therapy, overall survival, and safety.

At baseline, the median age in the combination, enzalutamide monotherapy, and leuprolide monotherapy arms was 69 years (range, 51-87), 69 years (range, 49-93), and 70 years (range, 50-92), respectively. Most patients in each arm were White (83% vs 83% vs 84%) and had a PSA doubling time of more than 3 and up to 9 months (80% vs 78% vs 77%). The median PSA doubling times were 4.6 months, 5.0 months, and 5.0 months, respectively. In terms of primary definitive therapy, 50% of patients in the combination and leuprolide monotherapy arms received radical prostatectomy and radiation therapy, along with 47% of the enzalutamide monotherapy arm.

Additional findings from the post-hoc analysis demonstrated that 3% of patients in the combination arm achieved an undetectable PSA at week 36 and 6% did so beyond week 37. In the enzalutamide monotherapy arm, these rates were 4% and 6%, respectively, and were 6% and 10%, respectively, in the leuprolide monotherapy arm.

Regarding MFS among patients who reinitiated treatment and achieved undetectable PSA, the hazard ratio for the combination vs leuprolide monotherapy was 0.52 (95% CI, 0.27-1.02; P = .052) and was 1.21 (95% CI, 0.68-2.15; P = .512) for leuprolide monotherapy vs enzalutamide monotherapy. In patients who did not achieve undetectable PSA levels after re-initiation, the hazard ratios for the combination vs leuprolide monotherapy and enzalutamide monotherapy vs leuprolide monotherapy were 1.00 (95% CI, 0.34-2.93; P = .995) and 1.31 (95% CI, 0.66-2.62; P = .436), respectively.

“Due to durable undetectable PSA levels, more patients had treatment suspension ongoing in the enzalutamide combination group versus [with] leuprolide alone after a median [time] of 4 years and 11 months,” Freedland noted in conclusion. “Independent of treatment type, achievement of undetectable PSA levels after treatment re-initiation was associated with improved MFS.”

Disclosures: Dr Freeland reported being a consultant for Astellas Pharma Inc., AstraZeneca, Bayer, Dendreon Pharmaceuticals LLC, Johnson & Johnson Innovative Medicine (formerly Janssen), Merck, Sumitomo Pharma America Inc. (formerly Myovant Sciences, Inc.), Pfizer Inc., and Sanofi.


  1. Freeland SJ, Giorgi UD, Gleave M, et al. Prostate-specific antigen dynamics from the phase 3 EMBARK trial: a post hoc analysis. J Urol. Published online May 1, 2024. doi:10.1097/01.JU.0001009540.33579.43.06
  2. FDA approves enzalutamide for non-metastatic castration-sensitive prostate cancer with biochemical recurrence. FDA. November 16, 2023. Accessed May 3, 2024.

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