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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU-medical oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today two fantastic GU-medical oncologists from the Huntsman Cancer Institute and the University of Utah, Dr. Ben Maughan and Dr. Neeraj Agarwal, who are here to talk to us today about a combination study of enzalutamide and radium that is recently reported updated data in The Oncologist. Thank you both so much for being here with me today.

Neeraj Agarwal: Thanks for having me, it's always such a pleasure.

Benjamin Maughan: Thanks Alicia, it's great to be involved today.

Alicia Morgans: Great. To get started, if we could hear from the two of you about how the study was initially designed and what the initial data was prior to this updated data, that would be fantastic. Can you share with us a little bit about the study design and that initial data, Dr. Agarwal?

Neeraj Agarwal: Very glad to. So radium as we know, radium-223, a bone modulating agent, which is known to be associated with overall survival and delay of skeletal events based on the Phase III registration trial or ALSYMPCA trial, which led to the approval of radium-223 for our patients with metastatic castration-resistant prostate cancer in 2013.

Around eight years ago, it was approximately 2014 or 2015 when we were using radium-223. We were not seeing any tangible markers of response to radium. As we know, radium is associated with overall survival benefits, but it does not lead to any immediate benefit in terms of PSA decline or radiographic progression-free survival. So we were looking for any markers of the response of radium and bone metabolism markers that were just published by Dr. Lucky Lara from UC Davis from a big SWOG trial, SWOG-0421 trial using atrasentan.

So we decided to do an investigator-initiated clinical trial of radium plus enzalutamide versus enzalutamide in patients with progressive metastatic castration-resistant prostate cancer. Enzalutamide was chosen over placebo because these patients had progressive metastatic disease and we didn't think placebo would be very appealing to me or my patients to be used in a clinical trial.

So after an initial lead-in phase of radium with enzalutamide, we randomized patients to radium plus enzalutamide versus enzalutamide alone. And there were a total of 47 patients who were included in the trial, enrolled on the trial. In the Clinical Cancer Research Journal, we published the original primary endpoint analysis. We showed the primary endpoint was met in terms of decreasing the bone metabolism marker [inaudible 00:03:05] which is a very important bone metabolic marker, was significantly lower in the combination arm. And it also correlated with a decrease in the PSA or improvement in the radiographic progression-free survival and so on.

So in this paper moving forward with a longer follow-up, we decided to look at the safety aspects of this combination and also secondary endpoints of efficacy, such as PSA-PFS2, such as radiographic progression-free survival and updated overall survival, even though the study was not powered for these endpoints.

Alicia Morgans: Fantastic, and I think these are especially important as we think about them in the context of PEACE-III, which is also looking at the same combination in this patient population.

So, Dr. Maughan, I'd love to hear from you what are your thoughts? What were your findings, the ones that were most recently reported in this updated analysis, particularly as they relate to safety? And then of course, as they relate to these other secondary analyses, recognizing that you weren't powered for these, but these are always very, very important analyses of course, with any clinical trial. So what did you find?

Benjamin Maughan: Yeah, thanks for the question, Alicia. So what we've seen as a general trend in prostate cancer over the last few years is that if we can find the optimal combinations to treat patients with, the clinical outcomes seem to be improved or prolonged like progression-free survival or metastasis-free survival. And so that was one thing we were interested to look for in this longer follow-up, was is this perhaps an optimal combination to improve the clinical outcomes for patients?

So you're right in that this study, being relatively small as a single institution investigator-initiated trial, was not appropriately powered to evaluate, for instance, a difference in overall survival between radium plus enzalutamide or enzalutamide alone. So when we looked at a number of these endpoints like time to next therapy or overall survival, there was no difference statistically between the two treatment arms. However, encouraging to me given the relatively small sample size of this study, we saw a consistent trend of numerical improvement favoring the combination across all of these endpoints compared to enzalutamide alone.

In particular, though, progression-free survival too was improved numerically and statistically with the combination over enzalutamide alone. And that I feel was particularly interesting because again, this is a relatively small study to look for any of these endpoints, even progression-free survival, across a 50 patient study that's randomized. So yeah, I was quite intrigued and interested by that effect. It is suggesting, but again not definitive proof, that this combination might be clinically more effective than enzalutamide alone.

The other really important question that has come up in the last few years, not just with radium but with all of these therapies, is the bone health of our patients. As we're finding more effective ways to control the disease, our patients are on this potent androgen suppression for more and more years and that's having a marked measurable negative effect on their bone health, resulting in increased fractures, et cetera. So we wanted to see if there was any suggestion of an increased risk to these patients with this combination compared to enzalutamide alone.

And fortunately, what we found is that there was no significant increase in fractures between the two groups. Also because radium is radiation-based, there is always a concern about myelodysplastic syndromes or bone marrow failure conditions. We did not see any suggestion of that in this trial. There were two fractures, one was related to trauma and the other one was a pathologic fracture, both were seen in the combination arm, but there was no suggestion, at least from my interpretation of the data, there was no significant increased risk to these patients. And again, no bone marrow failure complications were observed of either.

I will say, for the most part, all of these patients were treated with bone protective therapies as well, so that likely had a positive impact on the results that we saw in this trial.

Alicia Morgans: And I think to that point, this was definitely different than what we saw in the very early days of PEACE-III. At least what we saw reported out from Bertrand Tombal and the team, is that prior to the initiation of essentially a recommendation, a very strong recommendation, not quite a mandate I think, but really a very strong safety letter recommendation for that trial that there were some fractures, perhaps with some more happening within the combination arm. But essentially after the initiation of this letter, a safety letter suggesting that all patients really did deserve to have bone health agents, as is standard of care, the rate of fracture and the significant skeletal event went down pretty substantially.

And we would love to hear your thoughts, Dr. Agarwal, on how this study really supports that, especially since all of these patients, or a majority of these patients, seem to be treated with bone health agents. Again, as per standard of care, we should all be doing this, so really it's just following guidelines.

Neeraj Agarwal: Absolutely. When I saw the data presented by Dr. Silke Gillesson at ASCO's 2021 annual meeting, they were quite startling results.  In the PEACE-III trial, which is a phase three registration trial, 560 patients, randomizing patients to radium plus enzalutamide versus enzalutamide alone. As you said after the results of the ERA-223 trial came up showing abiraterone plus radium was associated with a much higher risk of bone fractures, the safety letter, which was issued to the patients on the PEACE-III trial, strongly recommending the use of bone-protecting agents, there was a 10 fold decrease in the risk of fracture after patients started getting bone-protecting agents after that letter was issued.

So before the letter was issued, 46% of patients were receiving bone-protecting agents in the combination arm and the enzalutamide arm. After the safety letter, 96% of patients were receiving the bone-protecting agents. And with the increasing number of patients receiving bone-protecting agents, we saw a tenfold decline in the risk of fractures.

So I think, obviously, our trial is a small trial, and I am convinced that because of our use of bone-protecting agents, we did not see any fractures, any high risk of fractures. However, the indication of what we are getting on the efficacy endpoints of this small trial, the very encouraging trends of radiographic progression-free survival, PSA progression-free survival being improved in our trial, I think this data bodes very well for the PEACE-III trial.

Alicia Morgans: I would agree and I think we are all very much looking forward to those particular results. And Dr. Maughan, I'd love to hear what are your thoughts in terms of your findings in this study in clinical practice? Does this have relevance in our clinical practice? Does it suggest that we can do these combinations with some hope of safety at a minimum and perhaps some efficacy? What are your thoughts?

Benjamin Maughan: Yeah, from the published literature in terms of real-world data, we know for a number of years now many physicians have been combining different therapies together: provenge plus novel hormonal therapies, radium plus novel hormonal therapies. My impression is that the combinations being done with radium have decreased after the ERA-223 data showing that the efficacy was not increased and there was a significant increase in toxicities or harm to the patient, particularly regarding their bone health and fractures.

Given that data, I think we should heed and really take caution from those results and it's probably best to avoid combining these therapies at this point in time until the ERA-223 data comes out. It is also important I think to understand that even though we oftentimes linguistically lump these together into a category of novel hormonal therapies, abiraterone and enzalutamide are not distinctly different medications and they do have similar, but again, distinctly different clinical outcomes, adverse effects, et cetera.

And so even though the ERA-223 trial was not positive in terms of improving clinical outcomes with a combination of abiraterone alone, that does not mean that the [00:13:13 inaudible] trial necessarily will have the same result. And again, I would echo what Dr. Agarwal was suggesting, our results do suggest there very well could be an improved clinical efficacy with this combination that we see with the PEACE-III trial.

So our safety data is encouraging, but in the context of the ERA-223 trial, I would urge caution with combinations that are not vetted through a phase three trial.

Alicia Morgans: I could not agree more. So as we wrap up, Dr. Agarwal, what are your final thoughts? What are your messages for viewers on this particular work?

Neeraj Agarwal: Bone protecting agents are one of the most important classes of drugs for our patients with metastatic castration-resistant prostate cancer. That would be my lesson from the PEACE-III study, from our study, and from the ERA-223 study in the past.

Alicia Morgans: And it's a very important message, thank you for sharing that. And Dr. Maughan, what is your message?

Benjamin Maughan: I think this emphasizes the value of ongoing research. There are still so many questions that we need to address to improve the care for our patients. And we need everybody involved to do that from these small institutional-driven studies to cooperative group trials, and certainly our industry partners as well. And I'm really proud and grateful to have participated in some improvements so far in the outcomes for our patients and I look forward to additional ones in the future.

Alicia Morgans: We are so appreciative of your contributions too and I thank you both for your time. I would emphasize, just as you both did, that bone health is supremely important in these patients who are on long-term androgen deprivation and intensified therapies that will lead to bone mineral density decreases no matter what you do in terms of calcium and vitamin D replacement. This will happen, and so it's important for us to be aware of that and to guard our patients against the complications that we can protect against.

And of course, to always remember that combining treatments outside of a clinical trial could lead us to a bad place. And so understanding those drug-drug interactions and making sure that we do what we can to understand and mitigate the complications from those combinations is absolutely something that we need to do as clinical trialists and as oncologists, of course.

So thank you both so much for your contributions, of course to the field as always, and for your time tonight. Thank you.

Neeraj Agarwal: Thank you very much.

Benjamin Maughan: Thanks, Alicia.