Neal Shore, MD, FACS, medical director at the Carolina Urologic Research Center in Myrtle Beach, South Carolina, discusses his study on the outcomes of men with high-risk, biochemically recurrent prostate cancer who suspended enzalutamide monotherapy treatment in the phase 3 EMBARK study. The abstract was presented at the 2024 ASCO Genitourinary Cancers Symposium. 

Transcript: 

Neal Shore, MD, FACS: Neil Shore, uro-oncology medical director, Carolina Urologic Research Center, Myrtle Beach, South Carolina.

Please give us a brief summary of the EMBARK study and its major findings.

Dr Shore: So as we've known that unfortunately, men with high-risk, localized prostate cancer 20 to 50 percent, regardless of if they have their primary treatment, radical prostatectomy or radiation therapy, will experience biochemical recurrence, oftentimes noted as PSA relapse, within 10 years of definitive therapy. And prior to the EMBARK trial we did not have any level 1 evidence for how to best treat these patients. Mostly they were treated with continuous versus intermittent testosterone suppression or androgen deprivation therapy, oftentimes with early generation AR pathway inhibitors like bicalutamide. The EMBARK trial look was more than a thousand patients globally. It was a three-arm trial for these patients with high-risk biochemical relapse, and by high-risk, biochemical relapse, they had to have had a PSA doubling time of less than or equal to 9 months, which is a very good correlate of biologic aggression. The three-arm trial, 355 patients approximately in each arm, one arm was enzalutamide monotherapy—that was open label—and the other two arms were blinded. Each arm and the other 2 arms received Q3 month leuprolide acetate. One arm got an oral placebo. The other arm got enzalutamide 160 milligrams, the dose that is approved now in mHSPC, nmCRPC. And throughout mCRPC.

Your abstract presented at ASCO GU examines the outcomes of men who suspended enzalutamide monotherapy treatment for high-risk, biochemically recurrent prostate cancer in the EMBARK study. Why was it important to examine outcomes in this population?

Dr Shore: Well, we previously showed in the trial that we published in the New England Journal of Medicine in October, and also patient-reported outcome data in New England Journal of Medicine evidence simultaneously in October, that the enzalutamide monotherapy arm, as well as the combination arm of LHRH and enzalutamide versus LHRH plus placebo, both of those arms—enza mono, enza combination—bested monotherapy LHRH. And with the primary endpoint being metastasis-free survival. Respectively, the combination had a hazard ratio 0.37, 0.62 hazard ratio for the enza monotherapy. Built into our trial design, at the end of 36 weeks, if your PSA nadir to less than 0.2 in any of the three arms you could undergo a treatment holiday, or an interruption of your therapy, and you didn't have to resume until your PSA was over 2. If you had had a radical prostatectomy or greater than 5, if you had had prior radiation therapy. So we wanted to see were there any differences in the three arms; particularly, I presented on the enza mono versus leuprolide mono for patients who had the interruption.

What were the outcomes of men who suspended enzalutamide monotherapy treatment in the EMBARK study? 

Dr Shore: Yeah. So at 37 weeks, of the 335 patients in the enzalutamide monotherapy arm, 304 patients, or 91%, had a treatment suspension. In other words, the PSAs were less than 0.2. In the leuprolide monotherapy of 332 patients, 240 patients, or 72%, were able to nadir below 0.2. So we thought that was very interesting. So more patients received a treatment holiday. Yeah. We further looked at those patients: Looking at the primary endpoint, which was metastasis-free survival, and it was fairly comparable for those patients that had a treatment suspension between enza mono and leuprolide mono. The hazard ratio was 0.84, but not statistically significant.

And additionally, when you, we, it's important to put that into the context for the patients that didn't have a treatment suspension: The hazard ratio favored the enzalutamide monotherapy of with a hazard ratio of .34. So it’s kind of early kind of an interesting finding. Putting it all together, we didn't find any new safety or adverse event signals.

The safety profile of enzalutamide is mentioned to be consistent with results from previous clinical studies. Could you provide more details on the observed adverse events, especially fatigue and hot flashes, and discuss how the safety findings compare with expectations and previous research? 

Dr Shore: Yeah, that's always important, you know, if you're gonna you know, go one treatment versus another, or add two treatments versus one, but in this case we reported on the most common treatment-emergent adverse events in the treatment-suspension group for enza mono versus leuprolide mono, as well as in the no treatment suspension, and what we found that the three most common treatment-emergent adverse events in the enza mono group, with and without suspension, were fatigue, gynecomastia, and arthralgia. It's important to note that no patients in the enza monotherapy arm were treated with any form of prophylactic prevention for gynecomastia, breast or nipple sequelae. So none received radiotherapy or aromatase inhibitors, or any subareolar or removal of breast tissue. And that's something that we're looking into in the future, and I think should be for a additional studies.

Looking forward, what are the implications of these findings on the treatment of prostate cancer?

Dr Shore: Well, I think, looking forward, we've seen in the EMBARK that whether you did combination enzalutamide-leuprolide, or enzalutamide monotherapy, either one of those treatments were better than monotherapy leuprolide. In terms of the primary endpoint of metastasis-free survival, we saw more treatment suspensions with enza mono versus leuprolide mono, but the MFS, or metastasis-free survival, was similar between those 2 arms. Of note, less than 10% of the patients in both of those treatment groups had undetectable PSA levels 2 years following their treatment suspension. So these patients clearly need to continue to be followed. We didn't see any additional safety signals, as we've talked about. I think there's opportunity in the future. If one were to consider enzalutamide monotherapy to have a review with patients and a shared decision-making discussion regarding prophylaxis regarding those additional or increased incidence of gynecomastia breast and nipple tenderness.