Editor’s Note: Prostate cancer is one of the most common malignancies in men. While prostate-specific antigen (PSA) monitoring remains a cornerstone for the early detection of biochemical recurrence (BCR), advances in imaging, the emergence of data on androgen receptor pathway inhibitors (ARPIs), and the development of stereotactic body radiotherapy have substantially reshaped the diagnostic and therapeutic landscape for patients with high-risk BCR following radical prostatectomy.
At a recent ESMO Congress, overall survival data from the EMBARK trial were presented, further confirming the survival benefit of enzalutamide in patients with high-risk BCR. Oncology Frontier – Urology Frontier invited Professor Neal D. Shore, Medical Director of the Carolina Urologic Research Center, to share insights into the background and key findings of the EMBARK study, as well as its potential implications for future clinical practice.
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Oncology Frontier- UroStream: The EMBARK study analyzed the benefit data of enzalutamide combination therapy in high-risk BCR prostate cancer. Could you share the relevant research background and its value for early intervention in prostate cancer?
Dr. Neal D. Shore：Eleven years ago, when we first designed the EMBARK trial, we had some very informative early data about patients who experienced biochemical relapse, or PSA recurrence, after undergoing prostatectomy, radiation therapy to the prostate, or both. Our data clearly indicated that if the PSA doubling time was quite slow, specifically over 10 to 12 months, we could safely monitor these patients, especially if they were negative on conventional imaging. Back then, our just only tools for imaging were CT scans and traditional bone scans.
At that time, we were already aware of the benefits of oral androgen receptor inhibitors, such as enzalutamide, from trials like AFFIRM and PREVAIL, which were published in the New England Journal of Medicine. These studies showed that adding an oral androgen receptor pathway inhibitor (ARPI) provided a clear additive benefit compared to just using androgen deprivation therapy (ADT) alone, whether it was post-chemotherapy mCRPC (AFFIRM) or pre-chemotherapy mCRPC (PREVAIL).
This led us to wonder: if testosterone suppression with ADT provides synergistic benefits, what would happen if we added an ARPI for patients with biochemical recurrence? We also had previous trials, like PROSPER, and others I was fortunate enough to lead, such as TERRAIN and STRIVE, which had shown promising signals of benefit. Additionally, earlier analyses, mostly from Johns Hopkins, revealed that patients who failed their initial treatment (prostatectomy or radiation) and had rapid PSA doubling times (less than 9 months) were much more likely to develop radiographic metastases. Therefore, we based our study design on patients with biochemical recurrence and a PSA doubling time of less than or equal to 9 months.
The trial included three cohorts. One cohort received traditional monotherapy with an LHRH agonist and a placebo. The main cohort compared LHRH plus enzalutamide against the control arm of LHRH plus placebo. A third cohort, which was open-label, received enzalutamide monotherapy without any sham placebo injections.
We presented these findings for the first time at the American Urologic Association meeting in 2023. The primary endpoint of the trial was metastasis-free survival. We demonstrated a robust hazard ratio of approximately 0.4 favoring the combination therapy (LHRH plus enzalutamide) over LHRH monotherapy, and a hazard ratio of about 0.65 for enzalutamide monotherapy outperforming LHRH monotherapy. At that time, two years ago, there was a trend towards improved overall survival, but it wasn’t statistically significant. We published these results in the New England Journal of Medicine, and regulatory bodies like the EMA and FDA approved the label expansion for enzalutamide to include high-risk patients with biochemical recurrence. However, the definition of “high-risk” wasn’t specified in the label. Later, further analyses in European cohorts suggested that a PSA doubling time of less than 12 months is generally accepted as the definition of high-risk BCR throughout most of Europe.
Here at ESMO 2025 in Berlin, Germany, we presented the 8-year follow-up data on overall survival. What we found was that the combination of enzalutamide and LHRH was superior to LHRH monotherapy, with a hazard ratio for overall survival benefit of 0.595. Looking at the overall survival follow-up for enzalutamide monotherapy versus LHRH monotherapy, while it was close, it did not reach statistical significance, although it still showed a trend towards a survival benefit.
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Oncology Frontier- UroStream: Based on this study and your clinical experience, would you initiate ARPI therapy in some patients with high-risk biochemical recurrence, rather than waiting until radiographic metastases develop, as has been the case in the past? What are the key pros and cons you discuss with your patients when making this decision?
Dr. Neal D. Shore：Our overall survival data were recently published in the New England Journal of Medicine, and the findings have been widely recognized by our peers. In clinical practice, I am confident when communicating with patients who develop a high-risk BCR after surgery and/or radiotherapy. In fact, a poster study presented at the 2025 ESMO Congress showed that patients receiving radiotherapy benefited significantly from enzalutamide monotherapy.
When discussing treatment options with patients at high risk of biochemical relapse in clinical practice, I no longer treat these patients with luteinizing hormone-releasing hormone (LHRH) agonists or antagonists alone. Instead, I tend to recommend combination therapy with enzalutamide, which can be combined with oral regorafenib, injectable degarelix, or other LHRH agonists or antagonists. Interestingly, many of these patients may have previously received ADT treatment due to radiotherapy or other reasons, and they were dissatisfied with that treatment experience. For example, they experienced severe hot flashes and fatigue. Moreover, we know that testosterone suppression is not only associated with cardiovascular metabolic syndrome but also leads to bone demineralization and has a significant impact on sexual function, such as causing decreased libido or loss of libido.
When I tell my patients that they could try enzalutamide monotherapy, they are very interested. In the data we have reviewed and published in New England Journal Evidence, patients on monotherapy enzalutamide have improved libido, some have better erectile function, certainly less bone demineralization due to the absence of testosterone and estrogen loss. There seems to be even some improvement or lessening of cognitive effects, although this can still be an issue since enzalutamide crosses the blood-brain barrier.
I regularly discuss with my patients through shared decision-making what is most interesting to them. One of the things we did not do in the EMBARK trial is implement any strategies to lower the risks of breast-related enlargement, nipple tenderness or pain. This was not part of the EMBARK trial nor was it included in our phase two trial involving over 200 patients who were on active surveillance with enzalutamide for one year and then reassessed with biopsies. The ENACT trial, which was published in JAMA Oncology, also showed similar results. Without a strategy to mitigate the elevated estrogen levels as well as the testosterone level with just monotherapy enzalutamide, you will see breast enlargement (gynecomastia) and nipple tenderness or pain. So for these patients now, much like in the high-dose bicalutamide experience, you can use a low dose of a selective estrogen receptor modulator known as tamoxifen. In my personal clinical experience, I offer 10 milligrams every other day, and it has been quite effective in reducing any of these breast-related symptoms. Sometimes prophylactic breast radiation can also be an option, 8 to 10 Gray, which can usually be given in a single day.
So yes, in response to your question, I believe that the standard of care for patients with high-risk biochemical recurrence, based on clinical benefits, is combination testosterone suppression therapies and enzalutamide. And for some patients, I review with them the option for enzalutamide monotherapy.
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Oncology Frontier- UroStream: Based on the available data, which characteristics of patients with high-risk biochemical recurrence (e.g., specific PSA doubling time, initial Gleason score) derive the greatest absolute survival benefit from enzalutamide treatment? How can we use biomarkers for precise patient selection?
Dr. Neal D. Shore：In the EMBARK trial, we were strict about enforcing a PSA doubling time of less than or equal to 9 months. Subsequent analyses have shown that even patients with a PSA doubling time of less than 12 months can benefit similarly from either combination therapy or enzalutamide monotherapy. For my patients with a PSA doubling time greater than 12 months, I simply monitor them without initiating treatment, as I don’t believe the risk justifies the benefit. For those with a definitely shorter doubling time, less than 9 months, and some with less than 12 months, I absolutely offer them the choice between combination therapy and enzalutamide monotherapy.
What’s available now, which wasn’t during the EMBARK trial, is PSMA PET imaging. All our patients were negative on conventional imaging, so we classified them as having non-metastatic castration-sensitive or hormone-sensitive prostate cancer. With more advanced PSMA PET imaging now accessible, if we detect one, two, three, or perhaps up to five lesions, there’s an opportunity for metastasis-directed therapy. However, we don’t yet have level one evidence from well-conducted phase 3 trials, though such studies are ongoing. The further question is, if we proceed with metastasis-directed therapy, like stereotactic body radiotherapy (SBRT) to selected lesions, would these patients also benefit from a short course of enzalutamide, an androgen receptor pathway inhibitor, and/or testosterone suppression? These are important questions that need monitoring.
One final thought: In the study, we implemented a dose interruption at 37 weeks, making it one of the first large trials to include an interruption period, of which I’m very proud. This allowed patients to have what we call a “holiday” from their therapy, which many truly enjoyed. Given that enzalutamide monotherapy can be so well-tolerated without lowering testosterone levels, we’re contemplating whether continuous therapy might benefit these patients, unlike those who received both enzalutamide and androgen deprivation therapy. Those patients had a very long period, over 15 to 18 months, without any therapy until they experienced a PSA relapse.
So, I believe there are still more answers to come and more research to be done. It’s crucial, and I would encourage all my colleagues in China who treat patients with high-risk biochemical recurrence (BCR), particularly those with a doubling time of 12 months or less, to consider combination androgen deprivation therapy and enzalutamide, or enzalutamide monotherapy, when initiating treatment. They should review with their patients the pros and cons of doublet versus single therapy.
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Oncology Frontier- UroStream: For patients who subsequently develop metastases, how does early ARPI use at biochemical recurrence affect their subsequent treatment options after they progress to metastatic castration-resistant prostate cancer? Is there a concern about cross-resistance?
Dr. Neal D. Shore：When patients progress from one line of therapy to another, we are concerned about clonal evolution and the emergence of certain resistant pathologies. Resistance poses a significant challenge in our discussions on treatment sequencing.
I firmly believe that as patients progress, it’s crucial to introduce therapies with novel mechanisms of action. As is often said, “The first shot is the best shot.” Therefore, intensifying treatment upfront while ensuring opportunities for patients to maintain a good quality of life is essential. If interruption of treatment is feasible and can be carefully monitored, I consider it a positive approach. However, if patients develop resistant disease after receiving ADT and an ARPI, I am not a strong advocate for switching to another ARPI. Of course, clinical trials remain an option, but their availability depends on the country’s healthcare system and available resources.
For a first-line mCRPC treatment following progression from a doublet of ADT and ARPI, several options exist. Taxane-based chemotherapy may be considered. Additionally, radiopharmaceuticals such as radium could be suitable, particularly for bone-predominant disease. There’s also an expanding field of radioligand therapies, primarily focused on PSMA-directed strategies. Furthermore, if the patient has an HRR mutation, they might be a good candidate for oral PARP inhibitor therapy.
Neal D Shore
