Is There an Expanded Role for Enzalutamide in Prostate Cancer?

Approximately 20% to 50% of patients who were definitively managed for prostate cancer will develop biochemical recurrence within 10 years.¹ According to a recent study published in the New England Journal of Medicine, enzalutamide may have a role in the treatment of biochemically recurrent prostate cancer.²

While the management of patients with biochemical recurrence is complex and supporting data are limited, patients are typically stratified by risk and subsequently undergo specific treatment, which can include salvage therapy, radiation, hormone therapy, and androgen deprivation therapy (ADT). Risk stratification is based on prostate-specific antigen (PSA) doubling time. A faster doubling time (<9 months) puts patients at high risk for rapid disease progression and increased risk of death due to prostate cancer.³ According to researchers, men with a PSA doubling time <3 months have a median survival of 6 years.⁴

The study authors noted that enzalutamide correlates with PSA level, which allows treatment response to be accurately monitored. Furthermore, the ARCHES and ENZAMET studies support the use of next-generation hormonal therapy, including enzalutamide, for patients with metastatic hormone-sensitive prostate cancer compared with ADT alone.^5,6 However, data supporting the use of next-generation hormone therapy for nonmetastatic castrate-sensitive biochemically recurrent prostate cancer are limited, which is why the authors chose to conduct the EMBARK trial, an important study evaluating the efficacy and safety of enzalutamide plus leuprolide and enzalutamide alone for patients with high-risk biochemically recurrent prostate cancer.

The authors noted this study had several industry sponsors, including Pfizer and Astella Pharma. Patients included in the study had biochemical recurrence and previous histologically or cytologically proven adenocarcinoma without neuroendocrine differentiation, signet cell features, or small cell features. Patients had high-risk disease, defined as a PSA doubling time ≤9 months and ≥2 ng/mL above nadir after radiation or ≥1 ng/mL after radical prostatectomy with or without postoperative radiation, serum testosterone of at least 150 ng/dL, and an Eastern Cooperative Oncology Group performance status score of 0 or 1.

Patients were excluded if they had undergone previous cytotoxic chemotherapy, had a history of predisposing risk factors for seizure, had image-associated evidence of metastases, or were considered to be a candidate for salvage radiation therapy (for patients who had previously undergone radical prostatectomy). The authors noted that “patients who had received previous hormonal therapy were excluded, except for those with the following indications: neoadjuvant or adjuvant therapy at the time of definitive radiation therapy for no more then 36 months and at least 9 months before randomization or a single dose or short course (≤6 months) of hormonal therapy administered for rising PSA levels at least 9 months before randomization.”

Patients were randomly assigned to either enzalutamide plus leuprolide, placebo plus leuprolide, or enzalutamide monotherapy. Leuprolide was given intramuscularly or via subcutaneous injection every 12 weeks at a dose of 22.5 mg, and enzalutamide was given at a dose of 160 mg daily. Treatment was stopped at week 37 if the PSA reached <0.2 ng/mL and was restarted if the PSA reached 5 ng/ml for patients who had not undergone radical prostatectomy or at least 2 ng/mL for patients who had undergone radical prostatectomy. Patients continued in their treatment arms until there was image-based evidence for recurrence or the patient had an unacceptable adverse event, seizure, or death. Investigators documented nonadherence in all cohorts.

The primary end point was metastasis-free survival (MFS) based on imaging evidence (computed tomography, magnetic resonance imaging, and whole-body radionuclide bone scan), assessed 4 weeks prior to the study and every 6 months after randomization, in the combination cohort compared with the leuprolide-alone cohort. Secondary end points included MFS in the enzalutamide-alone cohort compared with the leuprolide-alone cohort, time to PSA progression, time to needing another antineoplastic agent, and overall survival. Additionally, authors investigated time to distant metastasis, resumption of hormonal therapy, development of castration resistance, symptomatic progression, first symptomatic skeletal event, and first deterioration in quality of life.

Patients were enrolled over a 3.5-year period (2015-2018) in 17 countries in nearly 250 centers. Approximately 355 patients were enrolled in each cohort. Median patient age was 69 years, median PSA doubling time was approximately 5 months, and median PSA level was 5.2 ng/mL; 83% of patients were White. Median follow-up was 60.7 months. A total of 12.7% and 25.7% of patients in the enzalutamide-plus-leuprolide and leuprolide cohorts, respectively, had disease progression or died. Five-year MFS was 87.3% in the enzalutamide-plus-leuprolide cohort and 71.4% in the leuprolide cohort.

Risk of metastasis or death was 57.6% (hazard ratio [HR], 0.42; 95% CI, 0.30-0.61; P<.001) lower in the combination cohort compared with the leuprolide-only cohort. In all prespecified subgroups, enzalutamide plus leuprolide contributed an MFS compared to leuprolide alone. A total of 17.7% of patients in the enzalutamide-alone cohort died or had disease progression. The 5-year MFS was 80.0%, with a 36.9% lower risk of metastasis or death compared with the leuprolide-alone cohort.

Regarding PSA progression, the 5-year progression-free survival was highest in the enzalutamide-plus-leuprolide cohort (97.4%) compared with the enzalutamide-alone (88.9%) and leuprolide-alone (70.0%) cohorts. Enzalutamide in combination or alone was associated with a lower risk of PSA progression (0.07; 95% CI, 0.03-0.14; P<.001; HR in the monotherapy group, 0.33; 95% CI, 0.23-0.49; P<.001).

The rates of being free from further antineoplastic therapy followed similar trends in the enzalutamide-plus-leuprolide (83.0%), enzalutamide-alone (75.7%), and leuprolide-alone (61.7%) cohorts. Time to requiring further therapy was also longer in the enzalutamide-plus-leuprolide cohort (HR in the combination group, 0.36; 95% CI, 0.26-0.49; P<.001; HR in the monotherapy group, 0.54; 95% CI, 0.41-0.71; P<.001).

Enzalutamide in combination and as monotherapy was associated with longer time to developing distant metastasis, symptomatic progression, and first symptomatic skeletal event. The authors also noted that it was associated with a lower risk of castration resistance and resuming hormonal therapy.

The 5-year overall survival was 92.2% in the enzalutamide-plus-leuprolide cohort compared with the enzalutamide (89.5%) and leuprolide (87.2%) cohorts. Patients who met criteria for undetectable PSA levels and treatment suspension included 90.9% for a period of 20.2 months in the enzalutamide-plus-leuprolide cohort compared with 85.9% for a period of 11.1 months in the enzalutamide-alone cohort and 67.8% for a period of 16.8 months in the leuprolide-alone cohort.

Regarding safety, 97% of patients experienced an adverse event, including hot flashes and fatigue. In the enzalutamide cohort, there was a higher rate of nipple pain and breast tenderness, as well as cognitive and memory impairments. Treatment discontinuation rates were 20.7%, 17.8%, and 10.2% in the enzalutamide-plus-leuprolide, enzalutamide, and leuprolide cohorts, respectively, commonly due to fatigue.

The authors looked at clustered events, which were similar in all groups, ranging from 80.8% to 86.1%, and included fatigue, falls, fractures, hypertension, and musculoskeletal events. Most were less than grade 3 in severity. The rate of seizures was 1.1%, 0.8%, and 0.0% in the enzalutamide-plus-leuprolide, enzalutamide, and leuprolide cohorts, respectively.

Until this study, good evidence supported the use of enzalutamide in metastatic hormone-sensitive prostate cancer. “The results of this trial showed that enzalutamide had clinical benefits in patients with high-risk biochemical recurrence after definitive treatment,” the authors concluded. “No new safety signals were observed. Enzalutamide plus leuprolide and enzalutamide monotherapy both resulted in significantly longer metastasis-free survival and a longer time to PSA progression and receipt of antineoplastic therapy than leuprolide alone, while [maintaining] overall quality of life.”

David Ambinder, MD is a urology resident at New York Medical College/Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

References

1. Kupelian PA, Buchsbaum JC, Elshaikh M, Reddy CA, Zippe C, Klein EA. Factors affecting recurrence rates after prostatectomy or radiotherapy in localized prostate carcinoma patients with biopsy Gleason score 8 or above. 2002;95(11):2302-2307. doi:10.1002/cncr.10977
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. Markowski MC, Chen Y, Feng Z, et al. PSA doubling time and absolute PSA predict metastasis-free survival in men with biochemically recurrent prostate cancer after radical prostatectomy. Clin Genitourin Cancer. 2019;17(6):470-475.e1. doi:10.1016/j.clgc.2019.08.002
4. D’Amico AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen MH. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst. 2003;95(18):1376-1383. doi:10.1093/jnci/djg043
5. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799
6. Stockler MR, Martin AJ, Davis ID, et al; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Health-related quality of life in metastatic, hormone-sensitive prostate cancer: ENZAMET (ANZUP 1304), an international, randomized phase III trial led by ANZUP. J Clin Oncol. 2022;40(8):837-846. doi:10.1200/JCO.21.00941