Enzalutamide in biochemically recurrent prostate cancer: design and rationale of the EMBARK study

This is the first in a series of podcasts examining the phase III EMBARK study. Our podcast right now is entitled “Enzalutamide in biochemically recurrent prostate cancer: design and rationale of the EMBARK study.” It was funded by Pfizer and Astellas. We had medical writing and editorial assistance which was funded also by the sponsors. And both myself and Dr. Woo’s disclosures can be viewed in the published podcast article.

In this first podcast, we’re going to discuss the background and rationale for the EMBARK study [1], including the unmet medical need for this patient population, specifically patients who have biochemical recurrence [BCR] or what some folks call a PSA [prostate-specific antigen] relapse, and some notable features of the study design. Henry, perhaps we could start by talking about the rationale of the EMBARK study?

Now, at the time of the study design for EMBARK, we had patients with nonmetastatic castration-sensitive prostate cancer [nmCSPC] with high-risk BCR typically receiving treatments based around risk stratifications [11]. Now in patients with BCR, PSA doubling time is one of the strongest predictors of metastasis and death. In patients with BCR after radical prostatectomy [RP], the risk of metastasis and mortality from prostate cancer increases significantly as the PSA doubling time decreases, from the highest level of >15 months to the lowest level of <3 months [6, 12, 13]. Now for those patients not receiving salvage treatment or who had BCR after salvage, the next step in the treatment journey was defining the optimal timing of systemic treatment, a decision which was made complicated by considerations around the efficacy of treatment versus potential side effects and impact on quality of life in a typically asymptomatic population [10]. When EMBARK was devised, the standard of care for these patients included systemic treatment with androgen deprivation therapy [ADT] and that could be in the form of orchiectomy, or treatment with a gonadotropin-releasing hormone [GnRH] agonist, such as leuprolide, or a GnRH antagonist. But there was no general consensus on the timing of optimal ADT as a standard of care; although, most patients were treated prior to metastases, especially if they were deemed to be at high risk of metastasis [1]. Now, as ADT with androgen receptor [AR] pathway inhibitors [ARPIs], such as enzalutamide, had been demonstrated to improve survival in patients with metastatic castration-sensitive prostate cancer—and we are, namely, talking about studies such as ARCHES and ENZAMET [14, 15]—there was a desire to evaluate these therapies early in the disease course, such as those patients with a high-risk BCR [1].

You know, we looked at previous literature about PSA doubling times, everyone realizing that fast PSA doubling times are really predictive of a much more aggressive and more advancing disease. And it was sort of all over the place how people were treating it, mostly with ADT as you pointed out. But still, there really was no great level 1 evidence in a phase III trial that compared just monotherapy LHRH [luteinizing hormone-releasing hormone] agonism (ADT) versus adding in an AR blocker, such as enzalutamide. And I think what we did in our study that was very innovative, was after discussions with regulatory authorities, they said, well, you should put in a third arm that didn’t include ADT [1].

So, and then the thing when we designed our study, as you well know, we only had conventional imaging, CT [computed tomography] scan and technetium bone scan [1]. Of course, with all studies and time, new things occur and in this case, the imaging—PSMA PET [prostate-specific membrane antigen positron emission tomography]—and we’ll talk about that later. But any other thoughts, Henry? Your overview was really awesome and I’ll get into a little bit more of the weeds of the design in a second.

As you mentioned before, one of the issues associated with trials that go over a long period of time, the goal posts can shift somewhat because you can see the development of other therapies. And, in the case of prostate cancer in particular, the explosion of improved imaging modalities and we’ve seen MRI [magnetic resonance imaging] improve enormously in its quality and our understanding of the technology, and of course PSMA PET—and I think we’ll talk a little bit more about that shortly—but I think that’s one of the big-ticket items for discussion.

Briefly, the inclusion criteria were patients with high-risk nmCSPC and BCR. They had either had RP, radiation therapy, or both [1]. And the patients were eligible for initial biopsy after primary definitive therapy; they had histologically, cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation small-cell features [1]. Other key inclusion criteria for the high risk, we said we were going to use a definition of PSA doubling time of ≤9 months, and an absolute PSA level of ≥2 ng/mL above the nadir after radiation or ≥1 ng/mL PSA after RP with or without postoperative radiation [1]. They had to have a baseline serum testosterone of at least 150 ng/dL at screening and an ECOG [Eastern Cooperative Oncology Group] performance status of 0 or 1 [1]. We looked at the rapid doubling time of ≤9 months as an inclusion criteria based on a lot of really nice work that was done, which demonstrated that this doubling time was a significant predictive factor in relation to developing metastatic disease and eventual deaths; and there are references for that for you to look at it in depth [6, 9, 12].

Although the definition of a high-risk BCR and the length of the doubling time used in EMBARK varies slightly compared to some recent treatment guidelines [16–19], such as the EAU [European Association of Urology] [18], PSA doubling time as a predictive factor is, nonetheless, a very common denominator for identifying these patients at high risk for progression. As I said, the EAU uses a doubling time of less than a year [18]. And similarly the ASCO [American Society of Clinical Oncology] guidelines define a high-risk BCR as less than a year [19]. And there’s different use of the pathological grades, ISUP [International Society of Urological Pathology], typically in both EAU and ASCO [19]. The AUA [American Urological Association] guidelines for BCR also uses a doubling time of less than a year, while noting that a doubling time of ≤10 months is associated with a high risk of metastasis and prostate cancer-specific mortality [16].

The exclusion criteria was based on conventional imaging, any distant metastases, and we typically used full-body CT scan, bone scan, occasionally MRI; prior use of hormonal therapy except in certain indications for neoadjuvant adjuvant therapy for radiation therapy primary patients no more than 36 months at least 9 months before randomization, or just like a single dose or short course of ≤6 months [1]. We excluded anybody who had prior chemotherapy, and invariably that would have been a taxane or other systemic therapy, except for the neoadjuvant adjuvant LHRH [1]. They were excluded if they had a history of seizure or predisposition of seizure, or any significant cardiovascular disease [1].

So, we had a really pretty good, robust inclusion–exclusion criteria. As we said earlier, it was a three‑armed trial, there was a 1:1:1 randomization: enzalutamide plus leuprolide, that was what we call the combination group; the placebo plus leuprolide, or the leuprolide alone group, and those were blinded; but then the unblinded, third arm was enzalutamide monotherapy, we call that the monotherapy group—we were not going to give patients a placebo injection [1]. So, I think everybody should appreciate that the dose of enzalutamide was the approved dose in more advanced disease of 160 mg a day and that was administered orally, of course, with or without food. And our Q [every] 3-month LHRH was leuprolide as a single intramuscular or subcutaneous injection, every 12 weeks [1]. We had a little over 1000 patients, 1068 to be exact, so about 355 in two of the groups, 358 in one of the groups [2]. So, a really pretty good number of patients to make our assessments.

What were the endpoints? The primary endpoint was metastasis-free survival [MFS] in the combination group versus the leuprolide alone group [1]. That was the primary endpoint, and this was selected as MFS had been demonstrated to be a strong surrogate for overall survival [OS] in localized prostate cancer prior trials [20]. Key secondary endpoints: MFS in the monotherapy enzalutamide group versus the leuprolide alone group; time to PSA progression; time to new antineoplastic therapy; and OS [1]. So, we’re continuing to collect that data and we look forward to reporting on the OS as a key secondary endpoint. We also did safety and patient-reported outcomes [PROs], including FACT-P [Functional Assessment of Cancer Therapy – Prostate], the BPI [Brief Pain Inventory] short form, and PROs were also assessed at baseline and at 12 week intervals [1, 3].

You know, I really thought this was a very robust study, a lot was packed into it. We had, as I mentioned, the inclusion–exclusion criteria, the primary endpoint. One of the key things maybe you want to talk about just before we do our takeaways, Henry, is we had an interruption, didn’t we? We had sort of what some people call a holiday at 9 months in all the arms, if you got below a PSA of <0.2 ng/mL [1]. But maybe you want to comment on that or any other thoughts regarding the endpoints?

So, just some of the key takeaways for Dr. Henry Woo and myself, EMBARK was a phase III global trial, prospectively designed, to really understand whether early treatment combination of enzalutamide–leuprolide or enzalutamide monotherapy in patients with high-risk BCR—those who failed surgery, RP, radiation, or both—could have better outcomes versus just a placebo and leuprolide, which was really the sort of the standard of care when we designed the study [1]. We really had baked in a key element of a PSA doubling time [1]. So, these were really the patients that multiple studies had demonstrated that if you had a doubling time of ≤9 months, these were at a significant predictive factor for progression, specifically, the development of metastatic disease; that’s why we chose that [1]. And as we mentioned, a lot of the guidelines now, they typically or more commonly use <12 months [16, 18, 19].

The key findings of EMBARK are going to be discussed in our second podcast with myself and Dr. Woo, and they have been published in the New England Journal of Medicine [2]. And so, based on the findings of EMBARK—and I think this is what we’re so proud of is that—enzalutamide was approved by the US Food and Drug Administration for nmCSPC with a BCR at high risk for metastasis [21]. And then, it’s also been approved by the Committee for Medical Products for Human Use, CHMP, of the European Medicines Agency, also known as the EMA, have also approved the use of enzalutamide as monotherapy or in combination with ADT for the treatment of our patients with high-risk BCR, who have nmCSPC who are not suitable for salvage radiation therapy [22]. A great pleasure to do this podcast with you, Henry. Thank you so much.