Enzalutamide in biochemically recurrent prostate cancer: key findings from subsequent analyses of EMBARK and their implications in clinical practice

Welcome everyone, I’m Steve Freedland, Urologist at Cedars-Sinai Medical Center, Los Angeles, California. It’s my pleasure to welcome you to the third in this series of podcasts examining the phase III EMBARK trial [Citation1–3]. I would certainly encourage everyone to go back and listen to the earlier recordings, if you’ve not done so [Citation4,Citation5], and today’s broadcast is entitled “Enzalutamide in biochemically recurrent prostate cancer: key findings from subsequent analyses of EMBARK and their implications in clinical practice.” This podcast was funded by Pfizer and Astellas, with medical writing and editorial support from the sponsors. We did use Pfizer’s AI [artificial intelligence] tool, MAIA, in developing this but we certainly take full responsibility for the content. Disclosures can be viewed in the published podcast. And I am delighted to be here, from my steering committee, member and a key player within the EMBARK study, Dr. Ugo De Giorgi.

Thank you and hello everyone, I’m Dr. Ugo De Giorgi, Clinical Oncologist from the Department of Experimental Medicine, University of Salento, Lecce, Italy.

It’s great to have you here, Ugo, it’s always a pleasure to work with you. Let me just give a little background here and I think people will be very familiar with this. EMBARK was an international, randomized, global, phase III clinical trial. We previously published the full results [Citation1,Citation2], as well as discussed the rationale and study design in the first podcast [Citation4]. And in the second podcast [Citation5], we reviewed the primary outcomes from EMBARK, which showed that in patients with high-risk biochemical recurrence [BCR] conventional-imaging–negative—what I like to call CIN prostate cancer, conventional-imaging–negative CT [computed tomography] and bone scan—that the early treatment with enzalutamide plus ADT [androgen deprivation therapy], leuprolide in this case (or what we call enzalutamide combination), or enzalutamide by itself (what we call enzalutamide monotherapy), both statistically and clinically meaningfully improved metastasis-free survival (MFS), which is metastasis or death, a surrogate endpoint for overall survival; as well as many key secondary outcomes relative to ADT alone [Citation1]. More recently, we’ve actually published long-term data from EMBARK showing that ADT plus enzalutamide significantly and really dramatically improved overall survival, whereas overall survival for monotherapy was numerically better than ADT but this did not reach statistical significance [Citation6]; and importantly we preserved quality of life, with no new safety signals [Citation1,Citation2].

So, that’s the background, but where we’re going to go today is we’re going to discuss key findings from subsequent analyses—that maybe didn’t necessarily make the headlines, that weren’t in the New England Journal of Medicine—but are really focused on clinically important secondary outcomes, including efficacy, safety, health-related quality of life, and looking at different subsets. We’re going to be discussing the clinical implications, as well as our own personal experience; we certainly encourage listeners to refer to guidelines. Let’s start out with, Ugo, your thoughts: what are the key findings from the subsequent analyses of EMBARK in terms of data on efficacy, safety, patient-reported outcomes? What are your thoughts on that?

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved enzalutamide, with or without leuprolide, as the first androgen receptor pathway inhibitor (ARPI) for the treatment of patients with nonmetastatic castration-sensitive prostate cancer and BCR at high risk of metastasis. With additional supporting evidence from the EMBARK subsequent analyses, it is crucial to discuss how these findings can inform shared decision‑making between patients and clinicians in real-world settings, including consideration of clinical, financial, and patient preference implications associated with enzalutamide treatment.

A notable consideration for shared decision-making in the BCR setting is the utility of molecular-targeted imaging, particularly PSMA-PET [prostate-specific membrane antigen positron emission tomography] scan. This is because PSMA-PET has improved performance in detecting early local recurrence and metastatic foci compared with conventional imaging, and is the preferred imaging modality after definitive therapy [Citation14,Citation19–21]. When should a patient with high-risk BCR undergo PSMA-PET scan?

Ugo, it’s a great question and that’s really one of the key questions I’ve gotten as I’ve gone around the world talking about EMBARK, is how do we layer PSMA[-PET] on top of that? So, it was actually the recent focus of a post hoc analysis of an international, multicenter, prospective PSMA-PET study that included patients either after surgery or patients having post-radiation recurrence but no evidence of metastatic disease on conventional imaging [Citation22]. And if we looked at patients who met the EAU criteria for low-risk BCR [Citation23]—so now we’re not talking EMBARK-like patients but low-risk patients per EAU guidelines—the PSMA[-PET] detected metastatic disease in about 24% of those post surgery and 37% post radiation [Citation22], so relatively modest. But if we looked at those who met the EAU high-risk criteria, 37% post surgery and 70% post radiation, so higher levels. If we look at the US and European guidelines, they really recommend risk-stratified decision-making regarding salvage local therapy and systemic therapies, and PSMA certainly can play into that [Citation14,Citation21]. And there was a study that actually looked at EMBARK-like patients, came out of UCLA [University of California, Los Angeles], and what it showed was that about 84% of these patients actually had PSMA-positive disease [Citation24]. So, we know a lot of these patients will have PSMA-positive disease and that can help certainly inform our salvage radiation approaches for those post surgery; as well as those with negative, where we’re really not left with a lot of salvage local options and we’re thinking more systemic disease [Citation14,Citation21]. That’s why I do think imaging is certainly here to stay, is very much incorporated into the management today of BCR, and we have a graphical abstract accompanying this podcast that helps outline some of the steps based upon what that imaging should show.

So, Ugo, I’m going to throw this out to you: so, if the PSMA-PET scan is positive or negative, what are the next steps and how does that influence things in terms of metastasis-directed therapy [MDT], and results from EMBARK, with enzalutamide, in patients with oligometastatic prostate cancer?

In patients with nonmetastatic castration-sensitive disease on conventional imaging and low-risk BCR, the preferred approach is observation. In comparison, for patients with BCR and high-risk features, ARPI-based treatment with enzalutamide with or without ADT is indicated as a recommendation based on EMBARK findings [Citation1,Citation14,Citation25]. This risk-adapted approach is also applicable to patients with negative PSMA-PET. However, a subgroup of these patients may have oligometastatic disease on PSMA-PET scans, and may benefit from a PSMA-PET–guided treatment strategy that uses combined systemic therapy and MDT with stereotactic body radiotherapy or stereotactic radiosurgery [Citation19,Citation26–29].

Treatment approach to oligometastatic disease with a negative CT component requires multidisciplinary discussions that focus on risk-stratified shared decision‑making [Citation30]. In this setting, for patients with high-risk characteristics, enzalutamide with or without ADT could be an option, similar to EMBARK, with the potential for adjunctive MDT. So, Dr. Freedland, when is radiotherapy indicated in the treatment pathway for high-risk BCR?

Yeah, it’s a great question, Ugo, one that we face all the time in the clinic. And certainly, emerging clinical trial data do support the benefits of combining the radiation with systemic treatment, including ARPIs like enzalutamide, in this high‑risk biochemically recurrent group and particularly those with a high Genome Classifier score, which is based upon Decipher, a test; those with high-grade disease; advanced tumor stage; shorter doubling time; higher PSA levels; and certainly those with obviously metastasis [Citation26]. So, there was recently a phase II SALV-ENZA study which included patients who had recurrence after radical prostatectomy and by adding enzalutamide to the salvage radiation, actually improved 2-year progression-free survival; and that was true of the overall population as well as the high-risk subgroups who had pathological T3 or positive margins [Citation31]. And there was another study, called the phase II FORMULA-509 trial, that looked at similar—high-risk BCR, post surgery—and they received salvage radiation with ADT, as well as looking at the combination with ARPIs—in this case, it was the combination of abiraterone with apalutamide—and adding the ARPIs improved 3‑year progression-free survival and MFS in those high-risk patients [Citation32]. So, you know, we’re still waiting for more follow-up from that, but I think we are starting to see some early evidence in these high-risk patients, not all BCR. And I think that’s a really important point, is we’re not talking really long doubling time, in which case, we don’t know that we need any systemic therapy; we’re really talking in the short PSA doubling time, high-risk patients. We’re starting to see this evidence starting to build that combining the two, really can give dramatic improvement for our patients.

And early in the podcast, we certainly talked about PSMA[-PET] detection rates and, you know, it’s important to note that EMBARK enrolled, again, high-risk BCR. So, Ugo, what do we know about PSMA-PET in EMBARK-like patients?

In the second podcast of the series [Citation5], Dr. Shore and Dr. Woo noted that EMBARK used conventional imaging, but highlighted that imaging technology and its application in prostate cancer have evolved since the start of the EMBARK trial, especially through the use of PSMA-PET scan.

Per the EMBARK protocol, the definition of metastatic disease was based on conventional imaging, because PSMA-PET scan was not a validated imaging modality in the BCR population when the trial was initiated [Citation3]. We can argue that, given the higher detection performance of PSMA[-PET] versus conventional imaging, a subset of patients in EMBARK could have had oligometastatic disease or widespread metastatic disease on PSMA-PET scan at baseline and, therefore, may have been candidates for additional treatments.

This possibility was explored in a post hoc analysis of prospective PSMA[-PET] studies that included patients with EMBARK-like characteristics [Citation24]. Patients had rising PSA levels after definitive therapy, doubling time of PSA of 9 months or shorter, and no evidence of metastatic disease on conventional imaging. In this EMBARK-like population who had a median pre-enrollment PSA of 2.8 ng/mL and a median PSA doubling time of 3.6 months, PSMA-PET detected oligometastatic disease (defined as <5 metastatic lesions) in 39% of cases and polymetastatic prostate cancer (including those with at least 5 lesions) in 7% of cases. Results were consistent across prior definitive therapy subgroups of primary prostatectomy, primary radiotherapy, and salvage radiotherapy.

Although we cannot rule out the possibility that some patients in EMBARK may have PSMA-PET–positive lesions, recently published EMBARK data demonstrate favorable long-term overall survival outcomes with enzalutamide combination versus ADT alone [Citation6], which supports the survival benefits of this approach in the overall high-risk BCR population.

Since enzalutamide with or without ADT is an approved treatment for this population, we need to discuss what are the criteria to select combination or monotherapy for patients with high-risk BCR, and what key points should be discussed to empower patients and caregivers to make informed choices? What is your opinion on this, Dr. Freedland?

Yeah, thanks Ugo, and, you know, a little bit of this was covered in the second podcast [Citation5] with Drs. Shore and Woo, highlighting that in EMBARK, there were differences in the clinical benefits and tolerability between combination and monotherapy relative to ADT [Citation33]. And obviously everything we do in the clinic is individualized decision-making, going through all the data, listening to the patients and what’s important to them. And so, with that in mind, we need to know the data to be able to discuss it with patients, right? So, EMBARK patients who received combination, in terms of side effects, had increased risk of hot flashes, falls, arthralgia—kind of pain in the muscles and bones—, hypertension relative to monotherapy [Citation1,Citation2]; and those who had monotherapy had better-preserved sexual activity, again really highlighting a key value to monotherapy. On the other hand, because what happens is on monotherapy, you’re not castrate, your testosterone actually goes up because of feedback inhibition and that testosterone gets aromatized to estrogen. So, the testosterone is going to drive that sexual activity, but estrogen is going to the breasts and lead to gynecomastia, breast tenderness, nipple pain [Citation1], which really leads to the next question: how can we help prevent these breast-related side effects of monotherapy?

Clinical trial data indicate that monotherapy is commonly associated with gynecomastia, breast pain or tenderness, and nipple pain across the prostate cancer spectrum [Citation1,Citation34,Citation35]. But we do not have the data on the prophylactic measures for enzalutamide-associated breast-related adverse events. In the absence of enzalutamide-specific data, prophylactic tamoxifen and/or radiotherapy, which have improved bicalutamide-induced breast-related adverse events with relative tolerability, can be considered as preventative strategies for monotherapy given the similar mechanism of action for enzalutamide and bicalutamide [Citation36,Citation37].

Yeah, it’s a great summary and that’s what I’m doing is really prophylactic—I think that’s the key word, Ugo, that you hit on—needs to be done before you start the monotherapy: breast irradiation and/or tamoxifen, anywhere between 10 mg daily to 10 mg once a week—I’ve heard all over the place, I don’t think we know.

I just want to close by thanking you, Ugo, for joining me today, Dr. De Giorgi. Really enjoyed the discussion with you, and I hope you listeners have enjoyed this discussion and we have provided you with some insights into how we’re taking the EMBARK data, the additional data that have come out, and how to use it in your clinical practice. And certainly, if you want to know more about EMBARK, I would encourage you to listen to the other podcasts in this series [Citation4,Citation5] and of course, take a look at the multiple publications we’ve had [Citation1,Citation2,Citation6–8,Citation12,Citation15–17,Citation37]. And thank you very much for joining us.