Enzalutamide Approved for Nonmetastatic Castration-Sensitive Prostate Cancer With Biochemical Recurrence: Stephen Freedland, MD
The FDA recently granted approval to enzalutamide (enza) for the treatment of nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence, based on the results of the phase 3 EMBARK trial. Following the approval, Oncology Data Advisor Editorial Board member Dr. Stephen Freedland, co-lead investigator of the trial, sat down to share more about its significance for patients with high-risk prostate cancer and biochemical recurrence.
Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, we're excited to be discussing this week's expanded FDA approval of enzalutamide for nonmetastatic castration-sensitive prostate cancer with biochemical recurrence. I'm joined by Dr. Stephen Freedland, who co-led the study which led to the approval. Dr. Freedland, thanks so much for coming on today.
Stephen Freedland, MD: Thanks for having me. It's certainly an exciting time to be here.
Oncology Data Advisor: For a little bit of background before we dive into the trial, what does biochemical recurrence mean in prostate cancer, and how is it generally treated?
Dr. Freedland: That's a great question. When we say biochemical, we typically mean prostate-specific antigen (PSA). For early-stage prostate cancer, to a certain degree, PSA is the "end all, be all." It's how we diagnose, and it's how we follow patients afterwards. Patients will typically get diagnosed with an elevated PSA, and we do a biopsy and find cancer. If it's higher-risk, we will do surgery with radiation. Then we follow the PSA afterwards, and we want that PSA to be super low. After surgery, it should be zero; after radiation, it should be very low.
But when it starts to rise—and we have different definitions of rise, but once it reaches certain thresholds—we now say that is biochemical recurrence, PSA recurrence, PSA relapse, or biochemical relapse. It goes by a number of different names, but that's what we're talking about—they've had surgery, they've had radiation, and now there's evidence that these things didn't cure the cancer. We do the traditional imaging, bone scan computed tomography (CT), which was done in this study, and we see nothing. The question is, what do we do for those patients? It's kind of been this quagmire unknown for a long time.
Oncology Data Advisor: What was the EMBARK trial investigating for this population?
Dr. Freedland: We know for these patients that typically we'd like to try and get a second round of salvage local therapy, maybe some salvage radiation in there. But eventually the PSA, as a marker of the tumor, keeps going up and up, and we're ready to start systemic hormonal therapy. It's kind of been our first line. Hormonal therapy dates back to the 1940s. The question is, can we improve upon that? That's what EMBARK set out to ask.
EMBARK enrolled patients with high-risk, meaning a PSA doubling times of less than nine months—those at the highest risk of developing metastases and dying of their cancer. They were randomized to androgen deprivation therapy (ADT) alone, which is the way we've been doing this for an awfully long time, versus ADT plus enzalutamide, what we call enza combination therapy. That was the primary analysis in the double-blind fashion. Then the really interesting part of EMBARK is that there was a third arm of enzalutamide monotherapy, which was enzalutamide without ADT, and that was also compared to ADT alone.
The primary outcome was looking at metastasis-free survival, which means survival without either developing metastases or dying. There's some pretty strong data that metastasis-free survival is actually a surrogate of overall survival in patients with localized prostate cancer. That was the goal: can we improve upon decades' worth of conventional wisdom that we need ADT, and can we move the bar for these patients?
Oncology Data Advisor: It sounds like a really important question to address. What did the results of this study show?
Dr. Freedland: In the primary results, the metastasis-free survival showed very, very dramatic delays with the combination therapy, and it actually reduced the risk of metastasis or death by 58%. This is really, really dramatic. If we look at the five-year rates of not having metastasis not dying, so being alive with no metastasis, the rate was 71% in the control arm and 87% in the combination arm. There were also really dramatic improvements that showed delays in time to PSA progression, time to metastasis, time to next subsequent therapy, and actually a suggestion of overall survival.
Even though it's very early—it's an interim analysis—the hazard ratio is 0.59 and the P value is 0.015. This didn't meet our threshold for statistically significant, but it's clearly moving in the right direction, most intriguingly if we look at the monotherapy. To me, that was kind of the known; I think a lot of us had very strong suspicions that combination therapy was really going to blow the socks off the ADT alone. The question was about the monotherapy. It was a little bit more of an unknown, a little bit more of a risk, but that also beat ADT alone with a 37% delay in metastasis or death. It also met the end points of time to PSA progression, time to metastasis, and time to next therapy. If we look at the interim overall survival, the hazard ratio is 0.78 and the P value is 0.23—clearly not statistically significant, but also at least moving in the right direction.
Oncology Data Advisor: It's so exciting to hear such impressive results. What do these results mean for the treatment of patients with prostate cancer and high-risk biochemical recurrence going forward?
Dr. Freedland: I think what it means is that we finally have therapies that can delay the cancer and delay progression. In the long run—we're seeing some early evidence of it, but we need to keep following the patients—we can actually make patients live longer. That's pretty exciting in this disease space of patients who have already undergone surgery and radiation with the hope that it would cure the cancer and it obviously didn't. That's a very challenging space in terms of dealing with someone who has such high hopes and aspirations of being cancer-free, and now they're told they're not, and the PSA is going up quickly and we don't know what to do. Many patients feel like it's a death sentence. We try to reassure them that it's a long natural history, but now we actually have therapies that can make it longer and delay that progression. That's a real comfort to both physicians and to patients. I think patients will want this kind of therapy to keep the tumor under control as long as possible.
Oncology Data Advisor: Definitely, that's fantastic. As physicians begin to prescribe it for this new indication, are there any adverse events of note with enzalutamide or other considerations to keep in mind with it?
Dr. Freedland: Absolutely. Enzalutamide is a drug that's been out for over 10 years now. We have a lot of experience with this drug in more advanced stages. The good news in this trial is that we found nothing new. There are side effects of this drug, and we saw them. We saw more hot flashes, more fatigue relative to ADT alone, a little bit more hypertension, and some more falls. We did see more cognitive and memory impairment. But importantly, if we look at grade 3 or higher cognitive impairment, it was less than 1%, which was identical to ADT alone. We did see a couple of seizures, but again, these are all known side effects of enzalutamide. I think the key thing is we didn't see anything new. With monotherapy, interestingly, we saw an equal amount of fatigue, but hot flashes were much lower. We saw more nipple pain and gynecomastia. I'd say the side effects are different between them. They're not necessarily less.
We did look at global quality of life and saw absolutely no difference across the three arms, which is really reassuring that we're not worsening quality of life. There was actually a statistically significant suggestion that sexual function was better preserved with monotherapy, whereas hormonal symptoms were slightly worse with the combination, which kind of makes sense, though the difference in time to deterioration was a difference of one day versus control. The side effects are different in that there are side effects, but I think at the end of the day, we can say we're not worsening quality of life and we're delaying tumor progression. It's a pretty strong statement that we can give to our patients—we're not going to make them feel worse, and we're hopefully going to help them live better and live longer by delaying they're progression.
Oncology Data Advisor: Awesome, that's great to know. I know you mentioned this is the interim analysis. Are there any additional directions that future analyses will be exploring?
Dr. Freedland: Yes, so one of the things that was really unique and intriguing about EMBARK was that at 36 weeks of therapy, patients' PSA values were checked, and if less than 0.2 ng/mL, patients could actually go off therapy. They got a treatment holiday. In the combination arm, over 90% of patients got this treatment holiday, over 85% receiving the combination, but only two-thirds receiving the ADT alone. The duration of being off therapy was longer in the combination arm. We're now starting to look at what the predictors are for determining who got that off-treatment cycle and who stayed off treatment long-term.
What's interesting is that if you look, for example, at the monotherapy, the testosterone there, you're not castrate. Once you go off the enzalutamide, you have normal testosterone levels. We saw that five years later it was about 5% of people whose PSA had not risen to that threshold to restart therapy.
They were essentially off therapy for five years with normal testosterone levels. The question is, who are those people? That's like winning the jackpot. You get eight or nine months of therapy—and yes, there are toxicities and side effects, I don't want to minimize that—but eight or nine months of therapy and then you're getting five years off therapy with treatment-free normal testosterone.
So, can we start to identify those patients? Right now, we're looking at that and really trying to understand that aspect. We're also digging into some of the secondary outcomes. In short, we're analyzing the data we have, but we're also continuing to follow the patients for overall survival and hope to have an update about that at some point in the future. That will hopefully be very exciting follow-up data.
Oncology Data Advisor: Awesome, it'll definitely be exciting to see those results going forward. As we wrap up, anything else you'd like to mention about either the trial or the approval?
Dr. Freedland: For 80 years, we've done hormonal therapy, and it's been castration. It started out with orchiectomy and estrogens, and then we had luteinizing hormone–releasing hormone (LHRH) agonist injections. We now have LHRH antagonist pills and injections. We have a lot of options, and they all bring testosterone down and they all work. What we're realizing, coming from the advanced stage, moving earlier and earlier, is that ADT alone for these high-risk tumors is not enough. You really need to intensify that ADT, which is ADT plus a novel hormonal agent. These novel hormonal agents, particularly enzalutamide in the EMBARK study, are so powerful that we may not even need ADT anymore.
Hopefully, we are nearing the end of ADT alone as a therapy. There are always exceptions—the older, sicker man where we need some therapy. He's not going to tolerate the more aggressive therapy as a 90-year-old on oxygen, but he has metastatic disease and needs something. There are always exceptions to every rule, but in general, we are hoping that ADT alone is going by the wayside. I think that's what this study shows us more than anything. Yes, it's an expansion of the label for enzalutamide, and it's an exciting option for patients, but I think it also provides the increasing recognition that ADT alone has a very minor role, if any, to play in prostate cancer now.
Oncology Data Advisor: It's so great to hear more about the trial, the approval, and everything that it means for patients with prostate cancer. Thanks so much for coming on today to talk about all of this.
Dr. Freedland: Thanks so much for having me. It's always great to chat with you, Keira.
About Dr. Freedland
Stephen J. Freedland, MD, is Director of the Center for Integrated Research in Cancer and Lifestyle and Associate Director for Education and Training at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute. He also is the Warschaw Robertson Law Families Chair in Prostate Cancer and a Professor in the Department of Urology at Cedars-Sinai in Los Angeles. Dr. Freedland also holds a Staff Physician appointment at the Durham VA Medical Center in Durham, North Carolina. Dr. Freedland has published over 700 articles and served on numerous American Urological Association and American Society of Clinical Oncology guideline panels for prostate cancer. His research interests include the role of diet, lifestyle, and obesity in cancer, cancer health disparities, and cancer risk stratification.
For More Information
Freedland SJ, de Almeida Luz M, De Giorgi U, et al (2023). Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med, 389:1453-1465. DOI:10.1056/NEJMoa2303974
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.