EMBARK data suggest durable PSA control is possible despite testosterone recovery

Data from a post hoc analysis of the EMBARK trial (NCT02319837) were presented at the 2026 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium in San Francisco, California,¹ offering insight into the potential for durable responses following a finite course of hormonal therapy in men with high-risk biochemical recurrence of prostate cancer. In a conversation with Urology Times^®, lead author Neal D. Shore, MD, FACS, medical director of START Carolinas and Carolina Urologic Research Center in Myrtle Beach, South Carolina, discussed the rationale for the analysis and how the findings build on previously reported results from the pivotal phase 3 study evaluating androgen receptor pathway–directed therapy strategies in this patient population.

The EMBARK trial evaluated 3 treatment approaches: combination therapy with enzalutamide (Xtandi) plus leuprolide, leuprolide alone, and enzalutamide monotherapy in men with high-risk biochemical recurrence after prior definitive local therapy. A distinctive feature of the trial design was a planned treatment suspension after 37 weeks for patients whose prostate-specific antigen (PSA) levels declined to below 0.2 ng/mL. This strategy allowed investigators to examine whether early, intensive hormonal therapy could induce durable disease control while also permitting treatment breaks that might reduce long-term toxicity associated with continuous androgen deprivation.

Previously reported findings from EMBARK demonstrated that both the combination regimen and enzalutamide monotherapy significantly improved metastasis-free survival compared with leuprolide alone (combination vs leuprolide, HR for metastasis or death, 0.42; 95% CI, 0.30-0.61; P < .001; enzalutamide mono vs leuprolide, HR for metastasis or death, 0.63; 95% CI, 0.46-0.87; P = .005).² The combination approach also showed a clear overall survival benefit (HR, 0.597; 95% CI, 0.444-0.804; P = .0006), according to data presented at the European Society for Medical Oncology (ESMO) Congress 2025.³ These results established androgen receptor pathway inhibition, either with combination therapy or monotherapy, as an effective treatment strategy for patients with high-risk biochemical recurrence.

The newly presented post hoc analysis further explored whether some patients achieving deep PSA responses could maintain prolonged disease control even after therapy was suspended and testosterone levels recovered, raising important questions about the possibility of long-term remission with limited-duration hormonal therapy.

Urology Times: What is the background/rationale for this post hoc analysis? What were the previously reported findings from EMBARK?

Shore: Our poster was titled “Are Long-Term Remissions Possible With Hormonal Therapy Only?” This is a post hoc analysis of the phase 3 EMBARK trial, and we were examining the sustained PSA levels less than 0.2 ng/mL despite testosterone recovery after treatment suspension. As many of our [readers] would know, the EMBARK trial assessed the efficacy of combination enzalutamide/leuprolide, also known as enza combo, vs leuprolide alone and also enzalutamide monotherapy, also known as enza mono. The trial demonstrated significant improvement in metastasis-free survival for enza combo and enza mono, and [an overall] survival [benefit] for enza combo.

One of the key things about EMBARK, and we started this trial about 12 years ago, was that we had a treatment suspension after 37 weeks in all 3 arms if your PSA fell below 0.2 ng/mL. We did this post hoc analysis to evaluate the proportion of patients who maintained sustained PSA levels less than 0.2 ng/mL, or even less than 0.02 ng/mL, despite achieving testosterone recovery during the treatment suspension.

Urology Times: What key results from the post hoc analysis were presented at ASCO GU?

Shore: We evaluated PSA nadir levels. Profound PSA nadir has, in multiple other studies, shown a significant prognostic impact for patients. We looked at those patients with less than 0.2 ng/mL, less than 0.02 ng/mL, and who had testosterone recovery after treatment suspension at 12, 24, and 36 months. We had a little bit of a nuanced breakdown in their T [testosterone] levels, whether it was 175 ng/dL, 250 ng/dL, or getting back to their baseline. That was in Figure 2 of our poster.

The bottom line was that at 3 years after treatment suspension, 3.7%, 1.4%, and 1.1% of patients in enza combo, leuprolide alone, and enza mono, respectively, had these profound PSA levels of less than 0.2 ng/mL and had T levels of 250 ng/dL or higher. Interestingly, 3.7% in the enza combo, 0.8% in the leuprolide alone, and 0.6% of the enza mono with PSAs of less than 0.2 ng/mL didn’t achieve testosterone recovery [to 175 ng/dL]. Another [finding was that] at 36 months, 4% of enza combo patients in the suspension group had PSAs less than 0.02 ng/mL, [as well as] 2.5% of the leuprolide group and 0.8% in the enza mono group. So that’s the really low PSAs, less than 0.02 ng/mL.

Urology Times: How should practicing urologists interpret the finding that approximately 1 in 25 patients achieved a sustained PSA level of less than 0.2 ng/mL with testosterone recovery at 3 years after only 9 months of enza/leuprolide?

Shore: These are what some people would call the “super responders.” Even though it’s a small percentage, you can say to the enza combos, [those receiving] enza/LHRH, that 1 in 25 got long-term remissions after only 9 months of treatment, and it lasted for 3 years, basically being off treatment for 3 years. It’s a remarkable finding—marked PSA declines after 9 months and then no treatment. That clearly speaks to a select group that has profound efficacy and had the benefit of returning to normal testosterone levels and would not have had the associated [adverse] effects of testosterone suppression. And 2% of the patients in the combo had less than 0.02 ng/mL with normal testosterone levels, so it’s a pretty remarkable thing if you get into that subgroup analysis.

Urology Times: Building on that, what do the EMBARK data suggest about the role for early treatment suspension in select patients with PSA levels less than 0.2 ng/mL?

Shore: One of the things that we learned from EMBARK was that intensification can be very beneficial, but also that patients could have a choice of just ARPI, androgen receptor pathway inhibition, vs testosterone suppression…. A very small percentage of these patients––1 in 25 for the combo, 1 in 100 approximately for just LHRH monotherapy, and 1 in 100 for the enza monotherapy––could have these rather remarkable “super responder” results after just…9 months of treatment. Oftentimes, patients will ask the question, “Am I going to have to be on this therapy forever?” At the end of 9 months, we can say, “Well, we’re going to hold therapy, and we’re not going to put you necessarily in danger. In fact, you may actually benefit rather dramatically.” I think it’s still always important to follow these types of patients who have rapid PSA doubling times, who have failed prostatectomy or radiation or both, and it then becomes all part of what we are talking a lot about these days—the importance of shared decision-making.

Urology Times: For patients who achieve a PSA less than 0.2 ng/mL but have incomplete testosterone recovery, how should clinicians approach follow-up and monitoring?

Shore: That’s a very important question. I think it really is still the same [way] of making sure you follow these patients every 3 months or so. You obviously have a little bit of flexibility. If they don’t get full testosterone recovery, I think it’s important to monitor their bone health and make sure they’re not having any issues in bone demineralization, so they may require some additional supplement[ation] of vitamin D and calcium. They may require a bone health agent. Of course, nutrition and exercise are important, but I think that’s probably the best answer right now. There are some patients who will ask, “Well, wait a minute, if I’m not fully recovering, would I add testosterone?” For my patients with high-risk BCR [biochemical recurrence], I’m not really comfortable with that right now, and that’s an area of additional investigation.

Urology Times: Is there anything else you would like to add?

Shore: It’s great for our patients as well as our clinician community to know that we have choices in our 20% to 50% of patients who have high-risk localized disease, who we’re not able to cure with surgery or radiation or both. We now have an option of combination enza with an LHRH or enza with ADT [androgen-deprivation therapy] vs enza alone. The MFS [metastasis-free survival] clearly bested LHRH alone. OS [overall survival] was demonstrably superior with combo enza/LHRH vs LHRH [alone], and we trended positively in enza mono vs LHRH mono. What you still see with the enza mono vs the LHRH mono, or even the combo, is you do have clear signals that those patients on the enza mono have some improved sexual function parameters, not only in their ability to have sexual performance, but also libido, and to some degree, a decrease in hot flash[es] and less bone demineralization.

This is another nice subgroup analysis to further strengthen the conclusions that we had when we first presented the data at a plenary session at the AUA [American Urological Association meeting] in 2023––that was the MFS data––and then, most recently at ESMO, when we presented the long-term survival data in 2025. Very proudly, and on behalf of all the investigators, this has now led to 2 separate New England Journal [of Medicine] papers.

Editor’s note: Neal D. Shore, MD, FACS, reports relevant disclosures with Astellas Pharma and Pfizer.

REFERENCES

1. Shore ND, De Giorgi U, Gleave M, et al. Are long-term remissions possible with hormonal therapy only? post hoc analysis of EMBARK examining sustained prostate-specific antigen (PSA) < 0.2 ng/mL despite testosterone (T) recovery after treatment (tx) suspension. J Clin Oncol. 2026;44(suppl 7):189. doi:10.1200/JCO.2026.44.7_suppl.189

2. Freedland SJ, de Almeida Luz M, De Giorgi U, et al; EMBARK Study. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465. doi:10.1056/NEJMoa2303974

3. Shore ND, de Almeida Luz M, De Giorgi U, et al. EMBARK: overall survival with enzalutamide in biochemically recurrent prostate cancer. Ann Oncol. 2025;36(suppl 2):S1629-S1630. doi:10.1016/j.annonc.2025.09.103