Advanced Prostate Cancer Practice Informing Data Presented at ASCO 2022 - Neeraj Agarwal

January 5, 2023

In this discussion, Alicia Morgans and Neeraj Agarwal highlight prostate cancer abstract key takeaways presented at the 2022 ASCO meeting. In the PSMA targeting and imaging space, they highlight the 3-year update TheraP data. In the PSMA testing space, the correlation of PSMA positivity and risk of biochemical recurrence after surgery.  Drs Morgans and Agarwal transition to highlight the impact of triplet therapy trials, specifically data from the ARASENS and PEACE-1 trials, and the last two abstracts they highlight include the post-hoc analysis of ARCHES trial and the overall survival update for the longer follow-up in the ENZAMET trial.


Neeraj Agarwal, MD, Clinical Research Innovation, University of Utah Health - Huntsman Cancer Institute, Salt Lake City, UT

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to be here with Dr. Neeraj Agarwal, where we are talking about ASCO 2022 and the take home points, the key messages from the prostate cancer track. Thank you so much for being here with me.

Neeraj Agarwal: I'm so glad to be here. Always an honor.

Alicia Morgans: Always an honor to talk to you too, and I love the way you digest the information. I know you've continued to think about it, have conversations, dig into the data. What is the first abstract you'd really like to talk about?

Neeraj Agarwal: I'd like to start with PSMA-based abstract, PSMA targeting and imaging. I think those are the most discussed abstracts this ASCO. Abstract 5000 presented by Dr. Ian Davis, where he presented the update on TheraP trial comparing lutetium-PSMA-617, or lutetium PSMA, versus cabazitaxel in metastatic castrate-resistant prostate cancer patients who had progressed after docetaxel chemotherapy. This is a 3-year update, and for your recollection, TheraP trial was a randomized trial comparing these two agents, lutetium PSMA versus cabazitaxel, in those patients who had high PSMA expression and no sites of FDG-positive disease and no sight of PSMA-negative disease. This is so important to realize that these eligibility criteria were very strict and made sure that they did not include any patient who did not have PSMA-positive disease.

What they saw with the first earlier report on the primary endpoint, that lutetium resulted in better PSA responses and better progression-free survival. Those were the primary endpoints. In this meeting, they talked about secondary endpoint of overall survival. And what we saw was lutetium and cabazitaxel both had similar overall survival, and technically speaking it, they used the word restricted mean survival time, 19.1 month with lutetium and 19.6 month with cabazitaxel. Statistically similar overall survival. So, nothing unexpected. This is a secondary endpoint. Sample size was 200, not a large trial, not powered to look for overall survival, but still pertinent data, in my view, because that tells me, first of all, lutetium PSMA is a better therapy from the perspective of quality of life, from the perspective of progression-free survival, PSA responses, and overall. However, cabazitaxel is also a valid treatment option in these patients, especially in those patients who do not have access to lutetium.

Alicia Morgans: I think that's a great takeaway and it's actually my takeaway too. I think it's also important to remember, just as you mentioned, that the patients in TheraP were a select group of patients. And so I believe when I spoke with Dr. Hofman about this, approximately 30% of the population that screened for this trial were ineligible because of those FDG-PET and PSMA PET requirements that were included for eligibility. So as a community are thinking about using this agent, we have to certainly have access to lutetium, but we also have to make sure that the patient is eligible to receive lutetium so that we can apply these data to those patients. And some patients are not going be eligible. Importantly, cabazitaxel, still an active agent and still seems to have similar overall survival. So, still a good choice, particularly for those patients who are not going eligible.

Neeraj Agarwal: Fantastic summary.

Alicia Morgans: And thank you, because I think that you have such a balanced view of this, and it is important, as patients are seeking to have good therapies too. Which is the next abstract that you really wanted to dig into?

Neeraj Agarwal: Well, I'll continue the theme with the PSMA, but this time I'll switch to PSMA testing or diagnostic use of PSMA-based strategies. I'd like to highlight the abstract 5088, which was presented by Dr. Jeremie Calais' group in UCLA. I want to take a step back and talk about a multicenter prospective phase III trial, which was an emerging trial of more than 700 patients that garnered gallium PSMA approval for patients with intermediate and high-risk prostate cancer who were undergoing radical prostatectomy and lymph node dissection. They used gallium 68 PSMA-11 PET scan for predicting or for identifying pelvic lymphoma metastasis prior to surgery.

So, Dr. Calais' group, this time, reported the correlation of PSMA positivity and risk of biochemical recurrence after surgery. And, not unexpected, but still, these are practice influencing findings in my view, this is a large trial, but 36% patients had PSMA PET and 41% patients recurred and 40% patients did not undergo salvage therapy. I'm giving you the overall description of the trial, but let me come to the point here. When they look at the biochemical recurrence-free survival, it was much better in those patients who had PSMA-negative scan prior to surgery at 33 months, compared to only 7.3 months biochemical recurrence-free survival in those patients who had PSMA-positive scans. Interestingly, patients who had both negative, meaning they had PSMA PET-negative disease and lymph node-negative disease, their biochemical recurrence-free survival was 46 months median compared to only 3 months if they had PSMA-positive disease and lymph node-positive disease.

Overall, my key takeaway from this trial results is that PSMA PET scan now is an integral part of workup for those patients who are undergoing radical prostatectomy for their intermediate and high-risk prostate cancer.

Alicia Morgans: I could not agree more, and I thank you so much for going through that. Sometimes, to describe these data can be challenging because these are quite technical, of course. These imaging studies that are really trying to look at the predictive values and all of that. But, what is very clear is that clinical outcomes are affected. When we have a PSMA PET-positive lesion, the patients are going to have, certainly, a shorter time to biochemical recurrence.

And so importantly, the folks on the NCCN guidelines have integrated PSMA PET scanning as something that can be used for baseline risk assessment in patients with unfavorable intermediate risk, localized prostate cancer through high-risk and very high-risk localized prostate cancer. So, in fact, I'm actually using this approach when counseling patients in my own clinic and absolutely have made treatment decisions and changes to try to overcome what was seen in Dr. Calais' study, which is this higher risk of recurrent disease. And certainly, as you said, if we just can get people to adopt the guidelines, we can probably get better outcomes for our patients. So thank you for bringing this up. Really emphasizes the importance of some of the recommendations already made. What is the next abstract you'd like to bring up?

Neeraj Agarwal: I'd like to bring up the abstract presented by Dr. Armstrong on the post-hoc analysis of ARCHES trial. So this was abstract number 5072. When he looked at the radiographic progression-free survival and PSA progression in patients with metastatic hormone-sensitive prostate cancer who were being treated on the ARCHES and results were really interesting to me.

What Dr. Armstrong showed, that 67% patients who were experiencing radiographic progression on treatment with antigen deprivation therapy with enzalutamide did not have PCWG2 defined PSA progression at the time of radiographic progression. The discordance was present also in the ADT-only arm, so it was not a phenomenon only with enzalutamide. So if you look at the ADT-only arm, which was the control arm of the ARCHES trial, 42% patients on the ADT arm did not have PCWG2 defined PSA progression at the time of radiographic progression. I personally thought these data were very influencing for my practice.

Alicia Morgans: I would agree too. Interestingly, I had the opportunity to present somewhat similar data from the ARAMIS trial, suggesting that there was also a portion of patients who were progressing without PSA progression, of course, having this metastatic progression. And this is a different risk, I would say, though, in a non-metastatic CRPC population than in the ARCHES population, which of course, is already metastatic, and some of them have high-volume disease, it's more aggressive disease.

And so to your point, ensuring that we catch their disease progression before they become symptomatic by pain, in particular is really important in my practice because we know pain progression is associated with a worse prognosis for these patients. Dr. Agarwal, how do you actually do this in your practice? Because as you said, it's clearly important. How do you try to capture these patients when guidelines don't tell us exactly how frequently we should be scanning if we don't see PSA rising?

Neeraj Agarwal: As I said, this is practicing influencing data for me. I was obtaining scans in hormone-sensitive setting once a year and I was mostly relying on the PSA progression in those patients who are not on clinical trials, partly because we see a lot of real-world patients who are not on trials and they're creatinine kidney function may not allow a CT scan every 3 months if I continue to administer intravenous contrast every 3 months.

Having said that, I think I will be more vigilant now based on these data and like to do scans at least twice a year. That's number one. And number two is, I would like to risk stratify my patients. So patients have bone-only disease, I would go with bone scans more often, and patients who have visceral metastasis, I'll push for CT scans more often. I'm really hoping that PSMA PET will become cheaper, more widespread available so that we won't have to worry about IV contrast in the near future.

Alicia Morgans: These are all good ideas and I think it's a clear call for studies, and maybe your group, which is such a really phenomenally talented group looking at real-world data sets, can help guide us and practice here. So we need more data, Dr. Agarwal. Find some for us and report for us so we can improve our outcomes for our patients. I think you had at least one more abstract that you wanted to share.

Neeraj Agarwal: Yes. And again, thank you for allowing me to share this last abstract. Again, I think this has impact in my practice in the sense that we have seen triplet therapy trials being reported recently. ARASENS trial and then PEACE-1 trial by Dr. Fizazi. And then there were doublets, which were presented over the last 3, 4 years, and I've never seen debate hotter about what should we use, triplet therapy, doublet therapy, and so on?

In the midst of this debate, we see a trial, the update of ENZAMET trial, ANZUP 1304 trial, being presented by Dr. Ian Davis, which actually presented not only the overall survival update for the longer follow up approximately 6 years, but also on the subgroup analysis of those patients who received docetaxel concurrently to enzalutamide. So, all I can tell you is, just for the quick recollection, ENZAMET was a large phase III trial in metastatic hormone-sensitive prostate cancer setting of more than 1000 patients, which showed that ADT plus enzalutamide was superior to ADT plus bicalutamide in patients with metastatic hormone-sensitive prostate cancer. It met this primary endpoint in 2019 by showing 33% improvement in overall survival with enzalutamide.

One of the unique aspects for our recollection of the audience was that patients were allowed to receive docetaxel during the protocol treatment, and the receipt of docetaxel had to be predetermined before randomization. And it was based on patient and physician's discretion. A total of 500 patients received docetaxel, which was approximately 45% of all patients randomized to the ENZAMET trial. And in this timely update, Dr. Davis and Dr. Sweeney's team reported that combination of ADT plus enzalutamide continues to be a factor and reduced risk of death by 30% compared to the control arm. Interestingly, in the subgroup of patients who received concurrent docetaxel chemotherapy, there was no improvement with enzalutamide when they were receiving docetaxel chemotherapy.

And then I saw a lot of debate going on, whether we should be using docetaxel with enzalutamide or not be using docetaxel, especially given triplet therapy data. A lot of debate on Twitter. I will come to the bottom line of this and at least I will try to settle this debate from the ENZAMET trial.

First of all, the receipt of docetaxel was completely determined by doctors and patients. It was not a randomized allocation of docetaxel. Number two, the trial was not powered to look at the subgroup analysis. So in my view, my take on this, enzalutamide is an effective drug for patients with metastatic hormone-sensitive prostate cancer and its effect on survival is independent of the receipt of docetaxel. To basically one statement, key takeaway from this trial is, androgen access inhibition remains the mainstream of treatment for majority of my patients who have metastatic hormone-sensitive prostate cancer.

Alicia Morgans: That is such a wonderful distillation of that data. Thank you for that, Neeraj, because I think we have to look at a trial to understand what that trial is telling us based on how that trial was designed, and we can't pick apart these trials, necessarily, and try to apply other questions just because we want to answer those questions. That this trial doesn't answer every question. It answers the question that you just explained, which is that enzalutamide does appear to improve overall survival when added to ADT, regardless of docetaxel exposure. And that's the take home message. And that is, of course, when compared to ADT plus that alternate AR targeted agent, nilutamide, flutamide, or bicalutamide, which are clearly inferior. So, really, that's the message. We can try to pick apart subgroups, we can try to say triplets might be better here or there, but this child does not cleanly answer all of those questions, though it certainly is hypothesis generating.

So thank you so much for really going through this data. It was exciting and always one of my favorite conversations to be able to speak with you and to pick your brain on the latest and greatest in ASCO 2022 in terms of the prostate track. Thank you so much.

Neeraj Agarwal: Thank you again. It was great to be here as always.
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