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Zachary Klaassen: Hi. My name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. Today on UroToday, we're going to be discussing a recent paper in JAMA Network Open entitled Physician Reasons For or Against Treatment Intensification in Patients With Metastatic Prostate Cancer. I'm delighted to be joined by Dr. Neeraj Agarwal, medical oncologist at the Huntsman Cancer Institute. Neeraj, thanks, as always, for joining us on UroToday.

Neeraj Agarwal: Thank you for having me, Zach. And we did this paper together, so that makes it even more enjoyable to talk to you about these findings. I think these are critical data. So let me start with the paper first.

Zachary Klaassen: Yeah. Tell us a little bit about how this paper is different than maybe some of these treatment intensification publications we've seen, not just in the United States but also across the globe. This is a little more in depth, and there are some nuances to this paper. So maybe just lay that out for our listeners first.

Neeraj Agarwal: Yeah. We together and with many other authors, we have published from multiple data sets that despite level one evidence from multiple phase three randomized trials showing that treatment intensification, or combination therapies of androgen deprivation therapy with androgen receptor pathway inhibitors, or docetaxel, or now triplet combinations and doublets, they significantly improve survival, both in a statistically significant fashion and a clinically meaningful fashion.

Despite that, we have consistently seen underutilization of doublets, or triplets, or the combination therapies, to put it simply, in our patients with metastatic hormone-sensitive prostate cancer. In this paper or in this project, we take a step forward and we really delve into why our colleagues are not using—not utilizing—the combination therapies in many of their patients, why there is a lack of implementation of level one evidence. And we thought it would be critical to understand the reasons behind underutilization rather than simply reporting underutilization, which we have done multiple times in the past. So that's the paper about.

Zachary Klaassen: Absolutely. So I'd love for you to walk us through just the study design and some of the key results from our study.

Neeraj Agarwal: So let me just walk you through the data. This is the paper you are talking about, where we have done it together with many other authors very well known in the field, including Dr. Freedland and Dr. George and many others—fantastic people—and with a lot of support from Pfizer and the team. So I'd like to first start with the key point: why there is underutilization of level one evidence. We know it is happening, but why?

Just to take a step back, this study surveyed 107 US-based physicians who took care of these patients with metastatic hormone-sensitive prostate cancer. Together, these 100-plus doctors took care of more than 600 patients with newly diagnosed metastatic hormone-sensitive prostate cancer. And then we looked at who used combination therapy—or in this paper, we are using the term “intensification therapy”—and who did not use intensification therapy.

So the objective was to find the reasons behind underutilization or the lack of implementation of level one evidence. And as I said, this is a sort of intervention study. It is not simply getting the data from the big websites or big databases. We actually surveyed the physicians who went back and looked at those patients they had treated in the last few years, and why they treated those patients in a particular fashion. So here is the overall snapshot of the type of physicians and patients and what therapies they utilized.

We can see here the group comprised both medical oncologists and urologists. If you look at the utilization of ADT plus ARPi or ADT plus chemotherapy—which was very low, actually, less than 5%, around 3% to 4% of patients were receiving ADT with docetaxel—the numbers were higher, about 27% of patients treated with ADT plus ARPi. Surprisingly, and of course with the caveat that these patients were treated between 2019 to 2022—so an older data set.

But let's keep in mind that docetaxel was approved for metastatic hormone-sensitive prostate cancer in 2014, so five years before these patients were treated. And abiraterone was already approved in 2018, and apalutamide and enzalutamide were approved in 2019. So we are talking about all those drugs being available in the clinic when these patients were being treated, and it was striking to see the low number of patients who received combination therapies or intensification therapies.

Then let's look at the reasons. And this is the most interesting part of this study, which actually is one of the reasons why the study has attracted so much attention—the reasons reported by the physicians for why they treated their patients the way they did. If you look at physicians who treated patients who did not receive combination therapies, they were worried about the side effects, or they were not sure if the guidelines endorsed those treatments.

If you look at the other reason—the third most common reason—they said, “We are familiar. Our personal experiences tell us that this is the best way to treat these patients.” Many doctors, many of our colleagues out there, both urologists and medical oncologists, were worried about the quality of life impact, so possibly combination therapy has an adverse impact on quality of life for these patients. Many physician colleagues were happy with their 50% reduction in the PSA, despite the fact that achieving undetectable PSA in our patients is known to be associated with a clinically meaningful and statistically significant improvement in survival.

Still, many physicians were happy with the 50% or 75% reduction in the PSA. And then lastly, easy administration of therapy. I can connect with some of our urology colleagues, who may have found administering docetaxel chemotherapy to be more difficult in their clinics. But again, ARPIs are oral therapies and may not be as cumbersome to be delivered in our urology colleagues’ clinic. But even medical oncologists thought it is easier to just give Lupron or androgen deprivation therapy injections.

This being the most important slide of this discussion, I'd like to highlight again that concerns about side effects, adverse impact on quality of life, the fact that they thought that these treatments are based on guidelines, and unrealistic PSA achievement or PSA reduction goals which are not consistent with what has been reported in the literature. And I think if you summarize all of that—and by the way, let me take a step back and also mention why ARPis were not prescribed:

We can understand docetaxel therapy may be considered too toxic by many of our colleagues, or many patients don't want chemotherapy. This is a known fact that in chemo—like chemotherapy—utilization is low, even in mCRPC settings. But if you just look at the ARPi, again, very similar concerns: adverse impact on quality of life or patients. Our colleagues were worried about the side effects, and they thought maybe the androgen deprivation therapy alone is endorsed by guidelines.

So what is the take-home message from this study? Number one, it is very clear the study—these data—have clarified that there is definitely a lack of awareness of level one evidence among many of our colleagues out there in the community. If we are concerned about quality of life, that is not based on evidence. Multiple studies have shown, published in big journals, that treating with ARPi upfront does not compromise quality of life, despite the fact that these patients are being treated with two different drugs. Actually, they live much longer without compromising quality of life.

Concerns about side effects: we know that overall, if you look at the TITAN study or even the ARCHES trial and many other trials—if you look at the side effects bother scale—it was not... overall, that scale captures how much you are bothered by the side effects, and it didn't show increased bother; patients were not more bothered by the side effects.

Anyway—and also, I would like to mention the PSA goals. We know from multiple studies now that a PSA of less than 0.2 nanograms per milliliter is associated with a very significant improvement in overall survival. Yet still, many of our colleagues were happy with a 50% reduction in the PSA goal, which frankly can be achieved by androgen deprivation therapy injections, and they may be wanting to keep those ARPis for the castrate resistance setting, which we know is not a valid strategy.

Again, from the crossover data from the TITAN trial, from the ARCHES trial, we know consistently that patients who actually crossed over at the time of the primary endpoint being reported—even those patients who did not start ARPi upfront and then started ARPi at the time of crossover without progressing—had better survival than patients who did not start ARPi until they had castrate-resistant disease.

So overall, bottom line, we have to improve the knowledge or awareness of these data among our colleagues, not only in the US. This is not a US problem. This is a worldwide problem. Multiple countries, even first-world countries, have these problems. So I think the key is to improve education, improve awareness of the data among our colleagues across the world.

Zachary Klaassen: Neeraj, excellent review of the data. There are so many things we could get into in terms of discussion. I want to focus on a couple of things, and you mentioned them in your presentation already. Education. The clinical guidelines certainly do say in certain situations you can use ADT alone, but there's so much information, so much highlighting, particularly in NCCN, which updates one, or two, or three times a year, suggesting the benefit of treatment intensification.

The PSA goals you mentioned—it’s not just good enough to get it down 50% or 70%. Our goal is a PSA undetectable, depending on how you define that, less than 0.2. So taking those two examples—and those were reasons for not treatment intensifying in our study—how do we educate the people that maybe aren't going to ASCO GU every year and aren't going to the big meetings? How do we educate these people about those two specific things, but also treatment intensification in general?

Neeraj Agarwal: First of all, I would like to just emphasize that we are not blaming anyone here.

Zachary Klaassen: Yeah.

Neeraj Agarwal: Our colleagues are very busy practitioners out there, taking care of hundreds, tens of different types of diagnoses. In medical oncology, for example, a given community oncology colleague sees patients with lung cancer, breast cancer, skin melanoma, prostate cancer, and many other cancer types in a single week, sometimes in a single clinic. On the other hand, even urology colleagues—if you look at how busy surgeons they are, including you, Zach—they're busy surgeons. You have these clinics, but there's limited time.

Zachary Klaassen: Yeah.

Neeraj Agarwal: And then you add to that the requirement that if you want to go to these meetings, you have to be away from your practice four to five days. You have to travel. And many of our colleagues don't have time to do that. And just to add another layer of complexity to that, not only do you have to be away from your clinic for five days, you have to really pay for the registration fee and the hotel accommodation and many other expenses that come with one meeting. And you talk about four or five meetings happening in a year where data are being continuously updated.

Zachary Klaassen: Yeah. The landscape is changing every meeting. I mean, it's incredible how quickly it changes.

Neeraj Agarwal: Yeah. And the last thing is if you go beyond the US, how many people can afford, especially in the emerging economies? We talk to our colleagues in many other emerging economies, and we consistently hear a problem of affordability, financial constraints of not being able to travel to these big meetings which are often happening in Europe or the US or other countries where it can be quite cost prohibitive for them.

So I think those are the issues. And the solution is to just bypass all those hurdles. And we are— as we are doing right now, as we have discussed—UroToday has one of the deepest reaches among urology and medical oncology communities in the world. So bypassing all those physical barriers and getting these videos, getting these data through podcasts directly to the colleagues out there, is one of the major ways or avenues of disseminating these data.

Zachary Klaassen: Absolutely. I think I want to take that answer a little bit further. So we're moving into 2025 now. UroToday, as you mentioned, we're going to be coming up on almost a quarter century of UroToday. You said, too, I mean, this is delivered to the emails. It's on social media. This will be broadcast to all the countries available and have social media and email access. So I'm going to put you on the spot. How does UroToday in 2025 continue to get that message out there—specifically treatment intensification and the importance of it—as we move forward into this new year?

Neeraj Agarwal: The most important thing is what we are doing right now, talking about the data that we need to improve awareness. And hopefully, as the trends are getting better for using combination therapies in the context of ADT plus ARPi, we are going to see the next set of challenges next year or this year actually in 2025, when we will be seeing multiple new phase three trials being reported.

The genomic biomarker-based therapies, like the CAPItello trial—we saw the press release. The press release mentioned patients who are PTEN-deficient by IHC profiling of the tumor. They had improved outcomes with capivasertib when added to ADT plus ARPi. I think we expect to see the data in the context of patients who have tumor or mutations or aberrations in homologous recombination repair pathway genes.

Then we will be seeing data from the PSMAddition trial. So we are barely catching up with ADT plus ARPi, and now we have another challenge in front of us of incorporating those therapies into the treatment paradigm. And one of the major challenges will be how to improve the genomic sequencing, next-gen sequencing, of those tumor samples.

Zachary Klaassen: Yeah.

Neeraj Agarwal: We know from a recent publication in JAMA Network, which we covered here in UroToday, that less than 35% of patients had comprehensive genomic profiling of their prostate tumors in 2023, when olaparib has been approved since 2019. So I think we have to consistently keep doing it. That's the number one message. One video will not suffice.

Number two, we have to connect with all those experts who are actually on the same team, who are working on generating these data and have been working for years to get these data out there, to get them on board. Social media, definitely—X and many other social media tools or handles. UroToday is doing a fantastic job. But we have to include other stakeholders—

Zachary Klaassen: Yeah.

Neeraj Agarwal: —such as patient advocacy. And then, of course, cost has remained a barrier. Hopefully, with the Inflation Reduction Act—hopefully, with the $2,000 cap on the copay of Medicare Part D patients—that may not be a problem for our Medicare Part D patients. But then, there are many patients who do not belong to that category. Copay will remain an issue for them.

So I think awareness, education, sharing the data with our busy colleagues out there in the community who don't have time to go to these meetings in different ways, and working with patient advocates, working with ASCO, PCF—again, we are working with PCF here—but ASCO, American Association of Cancer Research, American Cancer Society, getting all those stakeholders on the same page. I think the sky's the limit there.

Zachary Klaassen: Absolutely. It's a great answer to a difficult question, I know. We could break down for another 30 minutes all of these complex issues. But again, on UroToday, experts like yourself giving your time and expertise, we're grateful for it. Maybe just a take-home message or two for our listeners, Neeraj.

Neeraj Agarwal: Take-home message is our colleagues out there in the real world are very busy practitioners. They are doing a fantastic job of taking care of the patients. But then, there's so much data coming up on a regular basis. It's hard to catch up with all those data, especially when you cannot attend five meetings in a year. So I think how to get these data to our colleagues out there in the real world is the key, and we should do our best to make it happen.

Zachary Klaassen: Yeah. Wonderful. Thanks so much, Neeraj, as always, for your time.

Neeraj Agarwal: Thank you very much for having me.