Table of Contents
- Key Points
- Background: Why This Research Matters
- How the Study Was Conducted
- Who Participated in the Study
- Key Findings: Metastasis-Free Survival
- Additional Results: PSA Progression, Treatment Delays, and Overall Survival
- Safety and Side Effects
- Quality of Life
- What This Means for Patients
- Limitations of the Study
- Recommendations and Next Steps
- Frequently Asked Questions
- Source Information
Key Points
- In a trial of 1,068 patients with high-risk biochemical recurrence of prostate cancer, adding enzalutamide to leuprolide improved metastasis-free survival compared with leuprolide alone.
- At 5 years, 87.3% of patients on enzalutamide plus leuprolide remained free of metastasis versus 71.4% on leuprolide alone, a 57.6% lower risk of metastasis or death.
- Enzalutamide alone also improved outcomes: 80.0% of patients remained metastasis-free at 5 years, compared with 71.4% on leuprolide alone.
- No new safety signals emerged, and quality of life was similar across all treatment groups in the trial.
- Patients should discuss their individual risk factors, including PSA doubling time and overall health, with their healthcare providers to determine the most appropriate treatment approach.
Background: Why This Research Matters
Prostate cancer remains one of the most common cancers affecting men. The American Cancer Society estimated that there would be 288,300 new cases of prostate cancer and 34,700 deaths from the disease in the United States in 2023.
After initial treatment for prostate cancer, many patients experience a rise in prostate-specific antigen (PSA) levels. PSA is a protein produced by the prostate gland, and rising levels can indicate that cancer has returned. This condition is called biochemical recurrence.
Within 10 years after definitive therapy for prostate cancer, approximately 20 to 50% of patients develop biochemical recurrence. A rising PSA level can indicate the presence of microscopic cancer cells that have spread to other parts of the body. This increases the likelihood of illness and death related to prostate cancer.
Doctors use a measurement called PSA doubling time to assess how quickly PSA levels are rising. A shorter doubling time means the cancer is growing more aggressively. Patients with a PSA doubling time of less than 9 months are considered to be at high risk for rapid disease progression and at increased risk for death from prostate cancer.
The outlook is particularly concerning for men with a PSA doubling time of less than 3 months. These patients have a median survival of only 6 years after biochemical recurrence.
Before this study, there was limited high-quality evidence to guide treatment decisions for patients with biochemically recurrent prostate cancer. Patients generally received a treatment strategy involving risk stratification, meaning doctors assessed their individual risk level to determine the best approach.
Previous research has shown that treatment intensification with next-generation hormonal therapies, such as enzalutamide, can prolong imaging-based progression-free survival and overall survival in patients with metastatic hormone-sensitive prostate cancer. These treatments also delay the development of castration-resistant prostate cancer and maintain quality of life compared with androgen-deprivation therapy alone.
However, evidence from phase 3 clinical trials regarding next-generation hormonal monotherapy (using a single drug rather than combination therapy) was lacking before this study. The EMBARK trial was designed to fill this gap. The EMBARK trial evaluated the efficacy and safety of enzalutamide plus leuprolide and enzalutamide monotherapy, compared with leuprolide alone, in patients with high-risk biochemical recurrence of prostate cancer.
How the Study Was Conducted
The EMBARK trial was an international, randomized, phase 3 clinical trial. This means patients were randomly assigned to different treatment groups, and the study was conducted at multiple locations worldwide. The trial was sponsored by Pfizer and Astellas Pharma.
The trial design was created by a protocol steering committee in collaboration with clinical development teams. The design and any amendments were approved by institutional review boards or independent ethics committees at each study site. The trial was conducted according to the principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines.
All patients provided written informed consent before participating. An independent, external safety monitoring committee composed of experts in prostate cancer, safety-data monitoring, and statistics conducted periodic monitoring of safety data.
Patients were randomly assigned in a 1:1:1 ratio to one of three treatment groups:
- Combination group: Enzalutamide (160 mg) taken orally once daily plus leuprolide (22.5 mg) given as a single injection every 12 weeks
- Leuprolide-alone group: Placebo (inactive pill) taken orally once daily plus leuprolide (22.5 mg) given as a single injection every 12 weeks
- Monotherapy group: Enzalutamide (160 mg) taken orally once daily without leuprolide
The combination group and leuprolide-alone group were double-blind, meaning neither patients nor their doctors knew which oral treatment they were receiving. The monotherapy group was open-label, meaning both patients and doctors knew they were receiving enzalutamide alone.
Randomization was stratified according to three factors: PSA level at screening, PSA doubling time, and whether patients had received previous hormonal therapy. This stratification ensured that these important characteristics were balanced across all three groups.
Treatment was suspended at week 37 if the PSA level dropped below 0.2 ng per milliliter. Treatment was restarted when the PSA level rose to at least 5.0 ng per milliliter for patients who had not undergone radical prostatectomy. Treatment was restarted when the PSA level rose to at least 2.0 ng per milliliter for patients who had undergone radical prostatectomy.
Patients continued their assigned treatments until imaging-based disease progression was confirmed by central review. Patients also continued until an unacceptable adverse event occurred, a seizure occurred, death occurred, or nonadherence due to protocol violation was documented. Patients or their physicians could also decide to discontinue the regimen.
The primary endpoint of the study was metastasis-free survival in the combination group compared with the leuprolide-alone group. Metastasis-free survival was defined as the time from randomization to the earliest objective evidence of imaging-based progression or death from any cause.
Imaging-based assessment of disease was determined by blinded independent central review using conventional CT scans or MRI and whole-body radionuclide bone scans. Patients were assessed for progression approximately every 6 months after randomization.
Key secondary endpoints included metastasis-free survival in the monotherapy group compared with the leuprolide-alone group, time to PSA progression, time to use of new antineoplastic therapy, and overall survival. Additional secondary endpoints included safety and time to various disease milestones.
For the primary endpoint, researchers calculated a target enrollment of 1,068 patients. Researchers also calculated that at least 197 events (metastasis or death) across the three groups combined would give the trial 90% power. This would detect a hazard ratio for metastasis or death of 0.58 for the comparison of the combination group with the leuprolide-alone group. The two-sided alpha level was 0.05.
All efficacy endpoints were analyzed using the intention-to-treat principle, meaning patients were analyzed according to their assigned treatment group regardless of whether they completed the treatment. Safety was assessed in the as-treated population, with patients evaluated according to the treatment they actually received.
Who Participated in the Study
From January 2015 through August 2018, a total of 1,068 patients at 244 sites in 17 countries were enrolled and underwent randomization. Of these, 355 patients were assigned to receive enzalutamide plus leuprolide, 358 to receive leuprolide alone, and 355 to receive enzalutamide monotherapy.
The data-cutoff date for the analysis was January 31, 2023. The median follow-up in all three groups was 60.7 months, meaning half of the patients were followed for at least this long.
To be eligible for the study, patients had to meet specific criteria. They had to have histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet-cell features, or small-cell features at the time of initial biopsy. They also had to have high-risk disease. High-risk disease was defined as a PSA doubling time of 9 months or less and a PSA level of at least 2 ng per milliliter above nadir after radiation therapy. Alternatively, high-risk disease was defined as a PSA level of at least 1 ng per milliliter after radical prostatectomy with or without postoperative radiation therapy.
Additional eligibility criteria included a serum testosterone level of at least 150 ng per deciliter and an Eastern Cooperative Oncology Group performance-status score of 0 or 1. This performance-status scale ranges from 0 to 5, with higher scores indicating greater disability.
Patients were excluded if they had undergone previous cytotoxic chemotherapy. Patients were also excluded if they had a history of seizure or a condition that may predispose to seizure. Patients were excluded if they showed evidence of distant metastatic disease on conventional imaging. Patients were also excluded if they were considered candidates for salvage radiation therapy after radical prostatectomy.
Patients who had received previous hormonal therapy were excluded, except for specific indications. These included neoadjuvant or adjuvant therapy at the time of definitive radiation therapy for no more than 36 months and at least 9 months before randomization. These also included a single dose or short course of hormonal therapy of 6 months or less administered for rising PSA levels at least 9 months before randomization.
The baseline characteristics were well balanced among the three groups. Most patients were White (83.2%). The median age was 69 years, with a range from 49 to 93 years. The median PSA doubling time was 4.9 months, with a range from 0.9 to 18.9 months. The median PSA level was 5.2 ng per milliliter, with a range from 1.0 to 308.3 ng per milliliter.
Approximately 30% of patients in each group had received previous hormonal therapy. Regarding primary definitive therapy, about 25% had undergone prostatectomy alone, about 26% had received radiation therapy alone, and about 49% had received both prostatectomy and radiation therapy.
Key Findings: Metastasis-Free Survival
The study met its primary endpoint. Enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival.
According to blinded independent central review, 45 patients (12.7%) in the combination group and 92 patients (25.7%) in the leuprolide-alone group had imaging-based progression or died. This means that nearly twice as many patients in the leuprolide-alone group experienced cancer spread or death compared with the combination group.
The 5-year metastasis-free survival rate was 87.3% in the combination group, with a 95% confidence interval of 83.0 to 90.6. In the leuprolide-alone group, the 5-year metastasis-free survival rate was 71.4%, with a 95% confidence interval of 65.7 to 76.3.
The risk of metastasis or death was 57.6% lower in the combination group than in the leuprolide-alone group. This difference was statistically significant, with a hazard ratio of 0.42 and a 95% confidence interval of 0.30 to 0.61. The P value was less than 0.001, meaning there is less than a 0.1% chance that this result was due to random chance.
The benefit with respect to metastasis-free survival was seen across all 12 prespecified subgroups of sufficient size for analysis. This included subgroups of patients with shorter PSA doubling times of 3 months or less and greater than 3 months to 6 months or less.
Enzalutamide monotherapy was also superior to leuprolide alone. According to blinded independent central review, 63 patients (17.7%) in the monotherapy group had imaging-based progression or died. The 5-year metastasis-free survival rate was 80.0% in the monotherapy group, with a 95% confidence interval of 75.0 to 84.1.
The risk of metastasis or death was 36.9% lower in the monotherapy group than in the leuprolide-alone group. This difference was also statistically significant, with a hazard ratio of 0.63 and a 95% confidence interval of 0.46 to 0.87. The P value was 0.005.
Additional Results: PSA Progression, Treatment Delays, and Overall Survival
The study also evaluated several secondary endpoints that provide additional insight into the benefits of enzalutamide-based treatment.
The estimated percentage of patients who were free from PSA progression at 5 years was 97.4% in the combination group, with a 95% confidence interval of 94.7 to 98.8. In the leuprolide-alone group, this rate was 70.0%, with a 95% confidence interval of 64.1 to 75.1. In the monotherapy group, the rate was 88.9%, with a 95% confidence interval of 84.6 to 92.1.
Patients in the combination group and the monotherapy group had a significantly lower risk of PSA progression than those in the leuprolide-alone group. The hazard ratio in the combination group was 0.07, with a 95% confidence interval of 0.03 to 0.14 and a P value less than 0.001. The hazard ratio in the monotherapy group was 0.33, with a 95% confidence interval of 0.23 to 0.49 and a P value less than 0.001.
The estimated percentage of patients who were free from new antineoplastic therapy at 5 years was 83.0% in the combination group, with a 95% confidence interval of 78.3 to 86.8. In the leuprolide-alone group, this rate was 61.7%, with a 95% confidence interval of 56.1 to 66.8. In the monotherapy group, the rate was 75.7%, with a 95% confidence interval of 70.6 to 80.0.
The time to first use of new antineoplastic therapy was longer in the combination group and the monotherapy group than in the leuprolide-alone group. The hazard ratio in the combination group was 0.36, with a 95% confidence interval of 0.26 to 0.49 and a P value less than 0.001. The hazard ratio in the monotherapy group was 0.54, with a 95% confidence interval of 0.41 to 0.71 and a P value less than 0.001.
Compared with leuprolide alone, both enzalutamide plus leuprolide and enzalutamide monotherapy resulted in a longer time to distant metastasis, symptomatic progression, and first symptomatic skeletal event. Enzalutamide plus leuprolide also resulted in a lower risk of castration resistance and resumption of any hormonal therapy than leuprolide alone.
No substantial difference was noted in the time to first deterioration of FACT-P total scores in the combination group or the monotherapy group compared with the leuprolide-alone group. The FACT-P is a quality-of-life assessment tool specific to prostate cancer.
Death occurred in 33 patients in the combination group, 55 patients in the leuprolide-alone group, and 42 patients in the monotherapy group. The 5-year overall survival rate was 92.2% in the combination group, with a 95% confidence interval of 88.7 to 94.7. In the leuprolide-alone group, the 5-year overall survival rate was 87.2%, with a 95% confidence interval of 83.0 to 90.4. In the monotherapy group, the rate was 89.5%, with a 95% confidence interval of 85.6 to 92.4.
Safety and Side Effects
No new safety signals were reported in this study. The safety profile of enzalutamide was consistent with that shown in previous clinical studies.
The median duration of treatment, excluding treatment suspension, in all groups was 38.7 months, with a range from 0.1 to 88.9 months.
More than 97% of patients in all groups had at least one adverse event. The most common adverse events, occurring in 10% or more of patients, in the combination group and the leuprolide-alone group were hot flashes and fatigue. The most common adverse events in the monotherapy group were also reported.
Treatment discontinuation occurred in 201 patients in the combination group, 146 patients in the leuprolide-alone group, and 157 patients in the monotherapy group. The most common reasons for discontinuation in the combination group were adverse events (73 patients), withdrawal of consent (32 patients), and radiographic progression (26 patients). In the leuprolide-alone group, the most common reasons were adverse events (36 patients), withdrawal of consent (26 patients), and radiographic progression (41 patients). In the monotherapy group, the most common reasons were adverse events (63 patients), withdrawal of consent (25 patients), and radiographic progression (37 patients).
At the time of treatment suspension and reinitiation, testosterone levels were reduced in both groups. This finding is consistent with the expected hormonal effects of the treatments.
Quality of Life
Quality of life was assessed using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) total score. This validated tool measures physical, social, emotional, and functional well-being specific to prostate cancer patients.
The study found no substantial between-group differences in quality-of-life measures. This means that adding enzalutamide to leuprolide or using enzalutamide alone did not appear to have a detrimental effect on patients' quality of life compared with leuprolide alone.
No substantial difference was noted in the time to first deterioration of FACT-P total scores in the combination group or the monotherapy group compared with the leuprolide-alone group. This suggests that the additional benefits of enzalutamide did not come at the cost of worse quality of life.
What This Means for Patients
This study provides important new evidence for the treatment of patients with high-risk biochemical recurrence of prostate cancer. The findings demonstrate that adding enzalutamide to standard androgen-deprivation therapy significantly improves metastasis-free survival compared with androgen-deprivation therapy alone.
The magnitude of benefit is substantial. At 5 years, 87.3% of patients receiving the combination remained free of metastasis compared with 71.4% receiving leuprolide alone. This represents a 57.6% reduction in the risk of metastasis or death.
Enzalutamide monotherapy also provided significant benefit compared with leuprolide alone, with 80.0% of patients remaining metastasis-free at 5 years. This finding is particularly important because it suggests that enzalutamide alone may be a viable treatment option for some patients.
The study also showed that both enzalutamide-containing regimens delayed PSA progression and delayed the need for new antineoplastic therapy. Both regimens also delayed the time to distant metastasis, symptomatic progression, and first symptomatic skeletal event. These are all meaningful clinical benefits that can impact patients' lives.
Importantly, the safety profile of enzalutamide was consistent with previous studies, and there was no apparent detrimental effect on quality of life. This means that patients can receive these treatments without experiencing worse quality of life compared with standard androgen-deprivation therapy alone.
The findings suggest that PSA could be a biomarker to identify patients who would have a good therapeutic response when strategies to deintensify therapy may be warranted. This could help doctors tailor treatment to individual patients.
Limitations of the Study
While the EMBARK trial provides strong evidence for the benefits of enzalutamide in high-risk biochemical recurrence of prostate cancer, several limitations should be considered.
The study population was predominantly White (83.2%), which may limit the generalizability of the findings to more diverse patient populations. The median age was 69 years, and most patients had an Eastern Cooperative Oncology Group performance-status score of 0, indicating they were relatively healthy at baseline.
The monotherapy group was open-label, meaning patients and doctors knew they were receiving enzalutamide alone. This could potentially introduce bias in the reporting of subjective outcomes, although the primary endpoint of metastasis-free survival was assessed by blinded independent central review.
The study was sponsored by Pfizer and Astellas Pharma, the manufacturers of enzalutamide. While the authors had full access to the data and were responsible for all content and editorial decisions, the sponsor involvement should be considered when interpreting the results.
The median follow-up was 60.7 months, which provides substantial data on metastasis-free survival. However, longer follow-up may be needed to fully assess overall survival differences between the treatment groups.
The study excluded patients with a history of seizure or conditions that may predispose to seizure, as well as those who had received previous cytotoxic chemotherapy. The findings may not apply to these patient populations.
Recommendations and Next Steps
Based on the results of the EMBARK trial, patients with high-risk biochemical recurrence of prostate cancer should discuss the potential benefits and risks of enzalutamide-based treatment with their healthcare providers.
Key points for patients to consider:
- Adding enzalutamide to standard androgen-deprivation therapy significantly improves metastasis-free survival compared with androgen-deprivation therapy alone.
- Enzalutamide monotherapy also provides significant benefit compared with androgen-deprivation therapy alone and may be an option for some patients.
- The safety profile of enzalutamide is consistent with previous studies, and there is no apparent detrimental effect on quality of life.
- Treatment with enzalutamide may delay PSA progression, the need for new antineoplastic therapy, and the time to distant metastasis and symptomatic progression.
- Patients should discuss their individual risk factors, including PSA doubling time and overall health status, with their healthcare providers to determine the most appropriate treatment approach.
Further research may help identify which patients are most likely to benefit from enzalutamide-based treatment and which patients may be candidates for deintensified therapy. The use of PSA as a biomarker to guide treatment decisions is an area of ongoing investigation.
Patients with high-risk biochemical recurrence of prostate cancer should be encouraged to participate in clinical trials when appropriate. Ongoing research continues to improve our understanding of the best treatment approaches for this condition.
Frequently Asked Questions
What is high-risk biochemical recurrence of prostate cancer?
Biochemical recurrence means your PSA level is rising after initial treatment, which can indicate cancer has returned. It is considered high-risk when the PSA doubling time is 9 months or less, or when PSA reaches certain levels after radiation or surgery. About 20 to 50% of patients develop biochemical recurrence within 10 years after definitive therapy.
What did the EMBARK trial find about enzalutamide for high-risk biochemical recurrence?
In a trial of 1,068 patients, adding enzalutamide to standard androgen-deprivation therapy (leuprolide) improved metastasis-free survival compared with leuprolide alone. At 5 years, 87.3% of patients on the combination remained free of metastasis versus 71.4% on leuprolide alone. Enzalutamide alone also helped, with 80.0% metastasis-free at 5 years.
What does a 57.6% reduction in the risk of metastasis or death mean for me?
It means that in the trial, patients who received enzalutamide plus leuprolide had a 57.6% lower risk of their cancer spreading or of dying compared with those who received leuprolide alone. This was a relative reduction, not an absolute one. The 5-year metastasis-free rate was 87.3% with the combination versus 71.4% with leuprolide alone.
What are the side effects of adding enzalutamide to androgen-deprivation therapy?
In the trial, no new safety signals emerged. More than 97% of patients in all groups had at least one adverse event. The most common side effects in the combination group and the leuprolide-alone group were hot flashes and fatigue. Treatment discontinuation due to side effects occurred in 73 patients in the combination group and 36 in the leuprolide-alone group.
Does enzalutamide treatment affect quality of life?
In the trial, quality of life was similar across all groups. Using a prostate-cancer-specific questionnaire, researchers found no substantial differences between those receiving enzalutamide plus leuprolide, enzalutamide alone, or leuprolide alone. This suggests that the additional benefits of enzalutamide did not come at the cost of worse quality of life.
Who was eligible for the EMBARK trial?
Eligible patients had confirmed prostate cancer without certain rare features, high-risk biochemical recurrence (PSA doubling time of 9 months or less and specific PSA levels after radiation or surgery), a serum testosterone level of at least 150 ng per deciliter, and a good performance status. They could not have had previous chemotherapy, a history of seizure, or evidence of distant metastasis on conventional imaging.
I have high-risk biochemical recurrence of prostate cancer with a rising PSA — when should I seek a second opinion about adding enzalutamide to my hormone therapy?
A second opinion is reasonable when your PSA is rising after prostatectomy or radiation and your PSA doubling time is 9 months or less, since that defines high-risk biochemical recurrence. In a large trial, adding enzalutamide to leuprolide improved 5-year metastasis-free survival to 87.3% versus 71.4% with leuprolide alone, and enzalutamide alone reached 80.0%. Because treatment can be suspended when PSA falls below 0.2 ng per milliliter, an independent review of your PSA history, imaging and pathology can help clarify which approach fits your risk factors. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original Article Title: Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer NEJM 2023
Authors: S.J. Freedland, M. de Almeida Luz, U. De Giorgi, M. Gleave, G.T. Gotto, C.M. Pieczonka, G.P. Haas, C.-S. Kim, M. Ramirez-Backhaus, A. Rannikko, J. Tarazi, S. Sridharan, J. Sugg, Y. Tang, R.F. Tutrone, Jr., B. Venugopal, A. Villers, H.H. Woo, F. Zohren, and N.D. Shore
Publication: The New England Journal of Medicine, October 19, 2023, Volume 389, Number 16, pages 1453-1465
DOI: 10.1056/NEJMoa2303974
ClinicalTrials.gov Number: NCT02319837 (EMBARK trial)
Funding: Pfizer and Astellas Pharma
This patient-friendly article is based on peer-reviewed research.
