FDA OKs Enzalutamide for Nonmetastatic Castration-Sensitive Prostate Cancer

• The FDA has approved enzalutamide (Xtandi) for the treatment of nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR).¹
• Enzalutamide is the first and only androgen receptor signaling inhibitor approved by the FDA in this intent-to-treat (ITT) population.
• The approval follows a supplemental new drug application and expedited development and review programs.

Enzalutamide has been approved for the treatment of patients with nmCSPC with high-risk BCR. With this approval, it becomes the first and only androgen receptor signaling inhibitor that is FDA-approved for this population.¹

The regulatory decision is supported by findings from the phase 3 EMBARK trial (NCT02319837) which demonstrated that enzalutamide plus androgen deprivation therapy (ADT), leuprolide, (n = 355) reduced the risk of metastasis or death by 58% vs leuprolide alone (n = 358; HR, 0.42; 95% CI, 0.30-0.61; P <.0001).^2,3

At a median follow-up of 60.7 months for the combination of enzalutamide plus ADT and 60.6 months with placebo, the median metastasis-free survival (MFS) was not yet reached (NR; 95% CI, NR-NR) with enzalutamide and NR (95% CI, 85.1-NR) with placebo. At 3 years, the MFS rates in the enzalutamide plus ADT arm and placebo arm were 92.9% and 83.5%, respectively, and the 5-year rates were 87.3% and 71.4%, respectively.

PC-3 human prostate cancer cells: © heitipaves - stock.adobe.com

For the secondary end point of prostate specific antigen (PSA) progression, enzalutamide/ADT was favored over placebo (HR, 0.07; 95% CI, 0.03-0.14), as well as the enzalutamide monotherapy arm vs placebo (HR, 0.33; 95% CI, 0.23-0.49). Time to first use of new antineoplastic therapy was also superior with enzalutamide plus ADT vs placebo/ADT (HR, 0.36; 95% CI, 0.26-0.49) and with enzalutamide alone vs placebo (HR, 0.36; 95% CI, 0.26-0.49).

At the time of the interim analysis, overall survival data were immature, but a trend toward OS improvement was seen with enzalutamide/ADT vs placebo (HR, 0.59; 95% CI, 0.38-0.91; P = .0153) as well as with enzalutamide alone vs placebo/ADT (HR, 0.78; 95% CI, 0.52-1.17; P = .2304).

"For patients who were previously treated for prostate cancer and had achieved remission, only to later receive the distressing news of disease recurrence with a risk of metastasis, the emotional toll can be profound," said Courtney Bugler, president and chief executive officer of ZERO Prostate Cancer, in a press release.¹ "This approval of XTANDI is a promising treatment option for the community, offering a ray of hope to patients and their caregivers during these challenging times."

About EMBARK

EMBARK was an international, randomized, phase 3 trial which included adult patients with prostate cancer with biochemical recurrence after local therapy who had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet-cell features, or small-cell features at the time of the initial biopsy before primary definitive therapy.²

All patients were required to have a PSA doubling time ≤ 9 months, screening PSA by the central laboratory ≥ 1 ng/mL if they have prior prostatectomy or at least 2 ng/mL above the nadir if they had prior radiotherapy, serum testosterone ≥ 150 ng/dL, and an ECOG performance status of 0 or 1.

Patients were randomized 1:1:1 to receive enzalutamide plus leuprolide, placebo plus leuprolide, or enzalutamide monotherapy. The 2 combination arms were double blinded.

Patients received either 160 mg of enzalutamide plus leuprolide (n = 355), 160 mg of enzalutamide monotherapy (n = 355), or placebo plus leuprolide (n = 358).

REFERENCES:

1. Pfizer and Astellas' Xtandi approved by U.S. FDA in earlier prostate cancer treatment setting. News release. Astellas. November 17, 2023. Accessed November 17, 2023.

2. Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465. doi:10.1056/NEJMoa2303974

3. 2. Shore N, de Almeida Luz M, De Giorgi L, et al. LBA02-09 EMBARK: A phase 3 randomized study of enzalutamide or placebo plus leuprolide acetate and enzalutamide monotherapy in high-risk biochemically recurrent prostate cancer. J Urol. 2023;210(1):224-226. doi: 10.1097/JU.0000000000003518.