Neha Vapiwala: Thank you so much for having me.
Neeraj Agarwal: So let's start with the first question. The PROTEUS trial demonstrated improvements in pathologic response, metastasis-free survival, and even free survival with perioperative apalutamide plus androgen deprivation therapy before and after radical prostatectomy. As a radiation oncologist, what was your overall impression of these results?
Neha Vapiwala: Well, first of all, thank you for having me on as a radiation oncologist to offer my perspective. And I'll start by congratulating the investigators, and of course, gratitude on behalf of all patients who contributed to the study. I know it's incredibly important work and a large trial that they conducted in record time, so really congratulations to all involved.
But I will say as a radiation oncologist, the first thing that struck me, and this is by no means a unique observation, I know many of my colleagues across the world had similar thoughts when first seeing the data, both at ASCO, and then, of course, the simultaneous publication, that this essentially answered a question of the value of adding apalutamide as an androgen pathway receptor inhibitor if you're using an intensified neoadjuvant approach, a perioperative approach in this patient population.
And according to at least the primary endpoint of both the path-CR and minimal residual disease and the MFS endpoint, which did evolve over the course of the study, and that's an important point for us to discuss because I know it's an important point of critique, but that in that setting, if you're going to use neoadjuvant or perioperative androgen deprivation therapy, that this study tells us adding apalutamide appeared to have some benefit, both in terms of pathologic complete response, in terms of reducing the rate of positive surgical margins, in terms of improving a composite MFS endpoint, with a big asterisk there. And that, to me, is pretty much what we learned. I think there are a lot of questions that it raised, some of which future analysis will answer and some of which will require additional study, and I think a ton of those questions that we could get into that it raised for a lot of us.
Neeraj Agarwal: Very well said. So next question is, many patients with high-risk localized prostate cancer can be treated with either surgery or with radiation-based approaches, so do these results change how you think about multidisciplinary discussions with patients, whether it is going to sway towards surgery versus radiation or that is the first discussion to happen, and then how does it affect the further discussions? Thank you.
Neha Vapiwala: Yeah. Well, I would say that based on the data that we've seen so far, we don't have anything to compare to current standard of care. So first, if you're talking about surgery in a high-risk or locally-advanced population with use of early salvage radiotherapy, with or without androgen deprivation therapy, in those patients that demonstrate postoperative biochemical recurrence, we don't have a proper comparator to that standard of care. If you look to radiotherapy plus long-term androgen deprivation therapy, a combination that's been shown in multiple randomized trials to have an overall survival benefit, in addition to many other survival and other important secondary endpoints, we don't have a comparator to that either.
So I think if you're talking about a patient in whom the decision for surgery has been made, and then there is some interest or concern possibly on a clinical trial or continued study of this perioperative systemic therapy approach, then these data might inform the conversation. But I think many of us are really reluctant to be able to say, yes, this should sway decision-making, because again, that fundamental issue of a lack of proper standard of care comparator remains, and that is at the heart of, I think, a lot of the critiques at this time.
Neeraj Agarwal: So even in PROTEUS trial... So let me take a step back. Which patients do you think are most likely to benefit from this perioperative approach? Are there particular clinical features that would make you especially enthusiastic about recommending this neoadjuvant or perioperative apalutamide with ADT in patients who are undergoing surgery?
Neha Vapiwala: Yeah. I mean, I think that's at the heart of this. First, when you think about the surgical population based on the current standard of care of treatment, where we reserve postoperative therapy for those that demonstrate early signs of recurrence, one of the key arguments for surgery is the avoidance of systemic therapy, the avoidance of medications that could impact testosterone, and of course, quality of life that follows.
And so I think a big question for all of us, including, of course, our surgical colleagues, is who are the patients that would want to still be interested in surgery, but then take on the androgen deprivation therapy, and now addition of an ARPI, and all of the side effects of that that can follow, including notably, a significant percentage, although it's not something that is often described, I think up to one in five patients did have continued testosterone suppression and did not demonstrate recovery. And so you're talking about really counseling patients who are interested in this approach, may have been particularly excited about surgery to avoid some of these systemic therapy concerns, and now making an argument for that, the selection is going to be key. And so first, that patient-oriented, patient-informed conversation, helping understand what their goals of care and expectations are.
And then, when you look to the data, I think that's where, really, there's a lot to be still answered within the PROTEUS subset. It was a definition that didn't quite meet traditional EAU or NCCN high-risk classifications. A lot of the patients were high-risk based on grade, not necessarily T3/T4 bulky tumors, where you might think, okay, multidisciplinary care is needed and you need this combination therapy to fight the bulky disease. And so really, in an era where we're increasingly moving towards biomarker-based stratification and genomics and defining who can most benefit, I think the opportunity is here to really use validated predictive biomarkers to really truly identify and answer the question that you just posed, is how do we make sure we're not over-treating? And this gets into the question of who is having even pathologic complete response based with ADT alone without even adding the ARPI? Are those patients being over-treated? So even within the population where you might use a perioperative systemic therapy approach, the combination is not necessary perhaps in all of them. So a lot of questions that we still, as I say, have to answer.
And I'll just put out there, the other thing that was interesting in this group, although I just said they were not really heavily leaning towards bulky tumors, in fact, many were clinical T1c and really just grade-driven, there were a decent number of patients, a decent percentage that were PSAs as high as 40 or more. And so we do wonder if the percentage of patients with perhaps micrometastatic disease, particularly since PSMA PET was not introduced as part of the composite MFS endpoint until midway through the trial, it does make you wonder if there's also some of that that we're seeing in terms of the treatment effect, that some of these patients had, in fact, micrometastatic disease. Maybe that explains, actually, why the event-free survival was frankly quite low in both arms, surprisingly low at four years.
Neeraj Agarwal: So even in the PROTEUS trial, postoperative radiation therapy was left to the investigator's discretion. So how do you see radiation therapy fitting into the management of these patients after surgery if this approach becomes widely adapted?
Neha Vapiwala: Well, I think that's where we really get into muddied waters. We, again, currently have a generally accepted standard of care that patients who undergo surgery, who have high-risk for locally advanced disease... And then, of course, there are nuances, by the way, about surgical pelvic lymph node dissection and the details of that, which also is a factor in PROTEUS in terms of extended versus not lymph node dissection. So even if you accept some of those unanswered surgical questions, if you talk about the standard as surgery followed by, again, early salvage radiotherapy, with or without androgen deprivation therapy, and nowadays, you can use a biomarker-driven approach for that decision, the reality is introducing now this proven early salvage radiotherapy in a population where there's testosterone suppression induced by this therapy with unclear benefit, and we know from at least the results so far that the four-year event-free survival in both arms of PROTEUS is, again, shockingly low, it does make you wonder, how would a radiation oncologist be able to properly assess for likely biochemical recurrence?
What is the confounding effect of the drug that's been given, and are we simply delaying the inevitable? And in a protocol where it wasn't mandated and it was left to investigators and left to sites, unfortunately, we can't learn much. What we do know is that the significant percentage, the vast majority of patients were not disease-free at four years, and yet the rates of postoperative therapy utilization were surprisingly low. So again, I think what you've asked is actually the very question we're asking ourselves, which is how do we manage these patients who are treated with this approach without a proper standard of care comparator, and then be able to apply what we know about early salvage radiotherapy in a population that typically is managed with surgery alone upfront? And usually, that suffices, that's the thing. And in fact, patients can do quite well with that. Second biochemical recurrence rates after salvage radiotherapy with or without androgen deprivation therapy, they're not zero, but they're actually quite low and quite favorable in well-selected patients. So I think we are, again, raising more questions than we're able to answer at the moment.
Neeraj Agarwal: Thank you for sharing those perspectives. So next is... We are already talking about this. So patients receive one year of intensified systemic therapy in addition to surgery. How do you weigh the improvements in disease control against the additional treatment burden and potential toxicities?
Neha Vapiwala: Yeah. Well, I know it's been said, I think the quote is no new safety signals, is how it was described. But if you look at the actual Grade 3/4 adverse event rates, it is pretty significant. It's almost 40% with apalutamide versus 31% with androgen deprivation therapy in the perioperative setting. It did lead to discontinuation rates that are not insignificant, over 7% versus under 3% without the apalutamide. And again, as I mentioned, one in five men failed to recover testosterone to over 200 nanograms per deciliter, and you have to ask yourself, particularly in some of the younger patients that we see who are candidates for surgery, if the difference in pathologic CR rates, again, not a surrogate endpoint that we can say translates into improved survival in a prostate cancer, is it really worth it for the patient to take on some of those side effects?
Even if most of those side effects are driven by rashes, there's not, I think, a way for us to necessarily justify the continued testosterone suppression, the potential long-term cardiometabolic implications of these therapies without further data, without further evaluation. And again, truly, I think awaiting that data, the longer term follow-up, the quality of life is going to be critical. And I will just point out there are adverse events to local therapy as well, and we do need to keep that in mind, particularly if these patients do go on to get salvage radiotherapy, what were some of the outcomes with the surgery itself in this kind of intensified upfront treatment strategy? And so grade two and higher urinary incontinence, that's important, those rates were up to 27%. And then, of course, erectile dysfunction and others. And I will just point out, serious events leading to death, again, low overall, thankfully, but 0.7% versus 0.1% with the apalutamide. So when you're having that conversation in tumor board or with a patient, I think all of this needs to be factored in.
And of course, we haven't even touched on the financial costs and thinking about being stewards of healthcare overall and healthcare utilization. Unless we are able to truly refine in which patients such an approach might make sense, it's really, I think, difficult to justify this as any sort of blanket new paradigm. And I'll just throw in there again, if the argument is, but the primary endpoints were met, we really do need to highlight that the MFS composite endpoint, while it's wonderful that PSMA PET was incorporated in this study, because many of our clinicians are asking for this, appropriately so, we want to modernize our trials, but in doing this, in adding the PSMA PET to the initial conventional imaging-based MFS endpoint, it really has made it very difficult to understand the treatment effect, other than to say over half of the events that were seen were by PET and they were PET-detected.
And so really, what you're seeing is event-free survival, you're seeing early detection, and whether that is correlated with overall survival is not known. We know that MFS by PSMA PET is not yet considered a surrogate the way it is by conventional imaging. And so yes, we've modernized things. Yes, we have some PSMA PET data. But really, the concern is a lot of what we're seeing as a positive signal and treatment effect is really just early PET detection and not something that's going to necessarily translate to an OS benefit. So again, in that context, can you take on those Grade 3/Grade 4 rashes, the testosterone suppression, the extra costs, and then the potential confounding of salvage therapies? That, I think, is a concern that many of us have been sharing.
Neeraj Agarwal: So I'll come to the closing question. If you had one key message for community oncologists, urologists, radiation oncologists watching this video, what would you want them to take away from the PROTEUS trial?
Neha Vapiwala: Sure. I think the PROTEUS trial, again, as I started by saying, congratulations to the investigators for really demonstrating the feasibility of this perioperative approach, and for those patients where with additional data and follow-up and really, truly biomarker-driven subgroup analyses to really try to better understand and define the different populations that were eligible for this study and who truly might benefit from this approach. As we seek to learn those data and await additional reports, we have to, I think, continue to follow the current standards of care and consider this an opportunity for additional investigation.
It's exciting to see that we can potentially, with path-CR, with minimum residual disease, see if we can gather more data towards understanding its impact in prostate cancer. Because the question remains, how come the path-CR and residual cancer burden hasn't had quite the translation to an MFS benefit as you might see in, for example, breast cancer or bladder cancer? So it just demonstrates that prostate cancer is, as we know, a different entity altogether, and there might be limits to just how much value even the surgical margin rate reduction yields, when at the end of the day, four years out, so many patients are not disease-free.
So I guess I would say to all of our oncologists, let's, again, continue to discuss these cases at tumor board, continue to have conversations with patients about what the study showed, but also the various questions that are not yet answered, and then work together to really think about how will we gather that data, not only from the PROTEUS dataset, but from real-world datasets, from existing data, and how do we do the best job possible in the future to compare to standard of care? And even as we await the PROTEUS substudy, which will compare to surgery alone, so that's at least one standard of care therapy that will be in the control arm, the primary endpoint, I believe, is still event-free survival. It's still a PSA-driven endpoint. So there'll be some caution that's needed as we interpret those data, and make sure we keep in mind that EFS is not the end-all be-all, and that we really need, as ICECaP and others have shown us, we really need a proper MFS by conventional imaging endpoint to say that OS benefit is down along the way.
So I think that's where ongoing conversations, open dialogue, and I think interpretation of all the positives and the questions remaining is important to our ongoing multidisciplinary care.
Neeraj Agarwal: Well, thank you, Neha, for sharing your insights on the PROTEUS trial.
Neha Vapiwala: Of course.
Neeraj Agarwal: It was a pleasure speaking with you, and I'm sure our audience will find your perspective both informative and highly valuable. So thank you.
Neha Vapiwala: Thank you for having me.