Enzalutamide Suspension in nmHSPC Does Not Affect QOL in EMBARK Trial

Stephen J. Freedland, MD

Global quality of life (QOL) was not meaningfully impacted by enzalutamide (Xtandi) suspension in in patients with biochemically recurrent (BCR) nonmetastatic hormone-sensitive prostate cancer (nmHSPC) responding well to enzalutamide, according to a data from the phase 3 EMBARK trial (NCT02319837) presented at the 2024 ASCO Annual Meeting.¹

The pivotal EMBARK trial was a double-blind, placebo-controlled study that included 1068 adult patients with nmHSPC with high-risk BCR.² Patients had all progressed following surgery or radiation and had a rapid PSA doubling time (<9 months). Patients were randomized in a 1:1:1 fashion to receive either oral enzalutamide monotherapy at a dose of 160 mg once daily (n = 355), enzalutamide 60 mg once daily in combination with intramuscular or subcutaneous leuprolide at a dose of 22.5 mg once every 12 weeks (n = 355), or placebo plus intramuscular or subcutaneous leuprolide at a dose of 22.5 mg once every 12 weeks (n = 358).

“One of the unique aspects, of EMBARK, however, is that patients got the treatment that they were originally assigned to for 37 weeks and then PSA was measured. If the patient had a good PSA response, defined as less than 0.2 ng/mL, treatment was actually stopped, and they stayed off therapy until the PSA rose to ≥2.0 ng/mL for those who had had radical prostatectomy (RP) or ≥5.0 ng/mL for those who had not had RP. And in these cases, they went back on their originally assigned treatment,” said presenting author 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.¹

According to Freedland, patients receiving enzalutamide were much more likely to get the treatment suspension. Ninety percent (n = 321) and 86% (n = 304) of the enzalutamide combination and monotherapy arms, respectively, had their treatment suspended compared with 67% (n = 240) of the leuprolide alone arm.

The goal of the post-hoc analysis presented at ASCO, Freedland explained, was to assess whether there was any impact on QOL in the patients who stopped treatment. Freedland et all collected data for this analysis by having patients complete patient-reported outcome questionnaires at baseline and every 12 weeks during the study until they had disease progression.

“And so, with this analysis, we essentially reset that week 37 value right before they stop treatment and essentially assign that as [time point] 0, and then look at the change [in QOL] going forward relative to that time point,” said Freedland. He added that if patients subsequently went back on treatment, they were no longer part of this analysis. “We only looked at patients who stayed on treatment suspension.”

A large number of patients started to go back on treatment after week 109, so Freedland et al used that as the ending time point for their analysis. This gave the researchers about 2 years’ worth of data.

Results on the Brief Pain Inventory Short Form (BPI-SF), which measures pain on a 0-10 range (higher score = worse pain), showed no meaningful changes in any treatment arm. Data for BPI-SF item 3 (worst pain in past 24 hours) showed scores of -3.3, -2.9, and -2.9 in the enzalutamide monotherapy, combination, and control arms, respectively.

There were also no significant changes in QOL as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) assessments. The changes in FACT-P total scores (scoring range 0-156; higher score = better) during the analysis time range were 22.3, 21.3, 19.5, for the monotherapy, combination, and control arms, respectively. On the FACT-P Physical well-being form (range, 0-28; higher score = better), the changes were 3.5, 3.3, and 3.0, respectively.

When looking at outcomes over the full time period of the analysis, results on the QLQ-PR25 (European Organization for Research and Tx of Cancer QoL Questionnaire-Prostate 25) also showed no significant QOL differences regarding sexual activity and urinary symptoms. QLQ-PR25 hormonal treatment–related symptom scores did rapidly improve across all arms shortly after treatment suspension; however, these symptoms worsened after week 97 and eventually returned to about their week 37 levels.

“On the one hand, this may seem surprising—we're taking a treatment with known side effects and stopping it, so you would expect quality of life maybe to improve a little bit. But if you actually go back to the original publication, on the quality of life, we had back in October in The New England Journal of Medicine Evidence,³ we actually saw that when we first started these treatments, it didn't negatively impact quality of life,” said Freedland.

“So, if I have a treatment that doesn't negatively impact quality of life, when I stop it, I'm not going to see quality of life go up, because it never went down in the first place. That's exactly what we see here is that quality of life is maintained…which really speaks to the relatively minimal impacts these therapies have on quality of life. Not to say there are not side effects and other things, but on global quality of life, there are no meaningful changes.” Freedland added.

Previously reported efficacy data from the primary analysis of the EMBARK trial showed that enzalutamide plus leuprolide reduced the risk of metastasis or death by 58% compared with placebo plus leuprolide in this patient population (HR, 0.42; 95% CI, 0.30-0.61; P < .001).2 The median metastasis-free survival (MFS) was not yet reached (NR; 95% CI, NR-NR) in the enzalutamide/leuprolide arm vs NR (95% CI, 85.1 months–NR) in the leuprolide alone arm. The 5-year MFS rate was 87.3% for those treated with enzalutamide plus leuprolide compared with 71.4% for those given leuprolide alone.²

Based on these findings, the FDA approved enzalutamide in November 2023 for use with or without a GnRH analog therapy for the treatment of patients with nmHSPC with BCR at high risk for metastasis.⁴

_References:

_{1. Freedland SJ, Gleave M, De Giorgi U, et al. EMBARK post hoc analysis of impact of treatment suspension (TxS) on health-related quality of life (HRQoL). J Clin Oncol. 2024;42(suppl 16; abstr 5005). doi: 10.1200/JCO.2024.42.16_suppl.5005}

_{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. Freedland SJ, Gleave M, De Giorgi U, et al. Enzalutamide and Quality of Life in Biochemically Recurrent Prostate Cancer. NEJM Evid. 2023;2(12). doi: 10.1056/EVIDoa2300251}

_{4. Pfizer and Astellas' XTANDI® Approved by U.S. FDA in Earlier Prostate Cancer Treatment Setting. Published online November 16, 2023. Accessed November 17, 2023. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-astellas-xtandir-approved-us-fda-earlier}