Enzalutamide in Men With High-Risk Biochemically Recurrent Prostate Cancer: Rationale and Treatment Considerations From EMBARK

Enzalutamide in combination with leuprolide (combination) and enzalutamide monotherapy were approved by the FDA (US Food and Drug Administration) and European Medicines Agency as treatment for patients with nonmetastatic castration-sensitive prostate cancer (PC) with biochemical recurrence (BCR) at high risk for metastasis. This approval was granted based on data from the global, phase 3 EMBARK study (NCT02319837) presented at the AUA Annual Meeting as a plenary presentation in April 2023 and published in The New England Journal of Medicine in October 2023. EMBARK demonstrated statistically superior and clinically meaningful improvements in metastasis-free survival for both enzalutamide combination (hazard ratio 0.42; 95% CI 0.30, 0.61; P < .0001) and enzalutamide monotherapy (hazard ratio 0.63; 95% CI 0.46, 0.87; P = .005) vs leuprolide alone in patients with high-risk BCR, with no new safety signals while maintaining quality of life (QoL).^1,2 The rapid FDA approval within 6 months of initial presentation of the primary results has resulted in several important clinical questions, which are discussed herein.

EMBARK STUDY PROTOCOL—THRESHOLDS FOR TREATMENT SUSPENSION AND REINITIATION

A unique feature of EMBARK was that patients were able to suspend treatment at week 37 if PSA levels were undetectable (<0.2 ng/mL at week 36). Patients reinitiated treatment when their PSA reached protocol-defined thresholds. PSA was quantified by a central laboratory with patients and study site investigators blinded to PSA values. For patients with prior radical prostatectomy, treatment reinitiation occurred when PSA increased to ≥ 2.0 ng/mL; for patients without prior radical prostatectomy, treatment reinitiation occurred when PSA increased to ≥ 5.0 ng/mL. These thresholds were high enough to ensure patients experienced as much time off therapy as possible, yet low enough to prevent the development of metastases.³ This was achieved by approximately doubling the PSA screening threshold for eligibility criteria for entry into EMBARK.

PSA PROGRESSION

During the conduct of EMBARK, 3 phase 3 studies in patients with nonmetastatic castration-resistant PC and PSA doubling time (PSADT) ≤ 10 months (SPARTAN, PROSPER, and ARAMIS) demonstrated improved clinical outcomes with apalutamide, enzalutamide, and darolutamide, respectively, vs placebo.⁴ Thus, treatment intensification with androgen receptor pathway inhibitors became standard of care for patients with nonmetastatic castration-resistant PC, and the sponsors wanted to inform investigators that patients may be eligible for these treatments. Beginning February 22, 2019, EMBARK investigators were notified by the central laboratory when patients had PSA progression with PSADT ≤ 10 months. As EMBARK was a global study, it was unclear which treatment regimen(s) would be available in specific countries, and the choice to intensify treatment should be a shared decision between patients and health care providers (HCPs).

RATIONALE FOR CONTINUOUS TREATMENT AT REINITIATION VS INTERMITTENT THERAPY

For patients who suspended treatment at week 37 and reinitiated treatment once their PSA reached protocol-defined thresholds, they did not suspend treatment a second time if they reached undetectable PSA. As such, the EMBARK study design was not intermittent therapy, whereby patients cycle on and off treatment depending on certain criteria; instead, it allowed for a single suspension for those with undetectable PSA. Intermittent therapy is currently recommended for the treatment of patients with high-risk BCR by the American Society of Clinical Oncology and an expert panel.^5,6 Intermittent androgen deprivation therapy (ADT) can be considered for patients who want to mitigate side effects of continuous ADT. These recommendations were based on a meta-analysis of 15 clinical trials that evaluated continuous vs intermittent ADT in advanced PC and demonstrated no significant differences in efficacy outcomes with minor improvements in QoL.⁷ However, many of these studies were conducted prior to the current understanding of risk stratification. For example, in patients with BCR, there was no consideration of PSADT. Thus, it is noteworthy that there were fewer PC deaths in the continuous ADT cohort vs the intermittent ADT cohort, though this was balanced with more non-PC deaths. As such, we determined that the benefit of intermittent ADT in patients selected to be high-risk was less clear and thus chose a single treatment suspension period for EMBARK. Future studies should explore the risks and benefits of true intermittent therapy with enzalutamide (with or without ADT) for high-risk BCR.

NEXT-GENERATION IMAGING

Patients were excluded from EMBARK if their disease was considered metastatic at baseline by conventional imaging assessed by CT, MRI, or chest x-ray and whole-body radionuclide bone scan. Since the first patient was enrolled in EMBARK in 2014, imaging technology has evolved rapidly with increasing sensitivity and selectivity to identify disease recurrence.⁸ In particular, next-generation imaging (NGI) technologies such as ⁶⁸galium–prostate-specific membrane antigen (PSMA) positron emission tomography have a detection rate of 51% at PSA from 0.25 to < 0.5 ng/mL, while conventional imaging has limited sensitivity at PSA values < 10 ng/mL.⁸ It is impossible to know if some EMBARK patients had metastatic disease at enrollment since NGI was still evolving at study start and was not universally available at all sites. Given that PSMA imaging is often used for patients with BCR, we recognize that the optimal management of PSMA-positive patients in the high-risk BCR setting is unclear, albeit an active area of research. A study evaluating a second-generation radiotracer, ¹⁸fluorine-PSMA-1007, had an 80% detection rate (140/175) in patients with BCR and median PSA of 1.6 ng/mL.⁹ For those in whom metastases-directed care is not considered an option and who are appropriate candidates for systemic therapy with no contraindications for enzalutamide, results from EMBARK support that these patients should be offered enzalutamide with or without ADT.

FACTORS TO CONSIDER WHEN CHOOSING BETWEEN ENZALUTAMIDE COMBINATION AND ENZALUTAMIDE MONOTHERAPY

It is important for HCPs to discuss the EMBARK results with their patients to determine the best individualized strategy, including management of treatment suspension and reinitiation, PSA progression, continuous treatment at reinitiation vs intermittent therapy, and the role of NGI. One important consideration is whether patients should receive treatment intensification with enzalutamide combination or enzalutamide monotherapy. Both enzalutamide combination and enzalutamide monotherapy vs leuprolide alone demonstrated clinically meaningful improvements in metastasis-free survival.¹ However, there were some differences that may be important for patients to consider in discussions with their HCP, such as treatment duration, adverse events (AEs), and QoL considerations. Notably, the overall rate of AEs and grade ≥ 3 AEs were similar in both enzalutamide arms. Contrary to our hopes, enzalutamide monotherapy was not associated with fewer AEs, but was associated with different AEs. For example, compared to enzalutamide monotherapy, enzalutamide combination had higher rates of hot flash (68.8% vs 21.8%), arthralgia (27.5% vs 22.9%), and hypertension (23.2% vs 18.9%). By contrast, relative to enzalutamide combination, enzalutamide monotherapy was associated with higher rates of gynecomastia (44.9% vs 8.2%), nipple pain (15.3% vs 3.1%), and breast tenderness (14.4% vs 1.4%).

Regarding the higher breast-related AEs with enzalutamide monotherapy, prophylactic treatments such as surgery, serum estrogen receptor modulators (eg, tamoxifen), aromatase inhibitors (eg, anastrozole), and radiation to breast tissue have prevented these AEs in prior studies.¹⁰ These treatments may have been available to patients in EMBARK; however, they were not required in the study protocol. Whether these approaches will prevent enzalutamide monotherapy–induced breast AEs requires further study. The mechanism of breast AEs with enzalutamide monotherapy is that due to lack of ADT, testosterone levels are increased 2-fold over baseline instead of being suppressed as observed with enzalutamide combination. This excess testosterone is aromatized to estrogen, leading to an imbalance in the estrogen-to-testosterone activity given that testosterone function is blocked by enzalutamide.¹⁰

Differences in the effect on serum testosterone were another key difference following treatment with enzalutamide combination or enzalutamide monotherapy with potential impact on treatment suspension duration and QoL.¹ During treatment suspension, the lack of testosterone suppression with enzalutamide monotherapy will stimulate PSA to quickly rise, leading to a shorter time until PSA meets the predefined thresholds for treatment reinitiation. Another potential difference for enzalutamide monotherapy, which we anticipate will be an important consideration for some patients, is enhanced preservation of sexual function.² Bone demineralization and sarcopenic obesity from androgen deprivation vs monotherapy androgen blockade will be analyzed in the future.

In summary, both enzalutamide combination and enzalutamide monotherapy delay disease progression while maintaining QoL and are now important therapeutic options for patients with high-risk BCR. The differences in efficacy, safety, and QoL between these 2 new options should be discussed with patients to identify the optimal strategy that meets their treatment goals and to achieve an empowering experience for the long-term management of patients’ chosen treatment.