Read the Full Video Transcript

Neeraj Agarwal: Welcome to UroToday. Today we have Dr. Arun Azad, Associate Professor and a medical oncologist specializing in genitourinary cancers at the Peter MacCallum Cancer Centre in Melbourne, Australia, to talk about his cutting-edge data he presented just last week at the 2024 ESMO Annual Meeting.

Arun Azad: Thank you, Neeraj, for the invitation to present today.

This is the slide deck that we presented last week at the ESMO Congress on UpFrontPSMA. This is the randomized Phase II study of sequential lutetium-PSMA-617 and docetaxel versus docetaxel in metastatic hormone-sensitive prostate cancer (mHSPC). This was an Australian multicenter study that ran at 11 sites, and some of the key investigators are listed here on this slide.

So the key takeaway points were that this was an investigator-led trial comparing lutetium-PSMA prior to docetaxel versus docetaxel alone in de novo high-volume mHSPC. The primary endpoint, which is undetectable PSA at 48 weeks, was significantly improved with the addition of lutetium-PSMA to docetaxel compared to docetaxel alone. There are also multiple key secondary endpoints, which we'll outline, that were also in favor of the experimental arm of lutetium followed by docetaxel. The significance of this study is it's the first randomized trial to demonstrate the efficacy of lutetium-PSMA in mHSPC.

We know that lutetium-PSMA is approved and recommended for metastatic castration-resistant prostate cancer, based on the VISION trial and the TheraP trial, also conducted in Australia. But in metastatic hormone-sensitive disease, its utility has been uncertain. The CHAARTED clinical trial, as we all know, established ADT plus docetaxel as a standard of care for de novo high-volume mHSPC. But outcomes for those patients unfortunately remain very poor. In fact, they do the worst of any patients with mHSPC. So our hypothesis was that if we add lutetium-PSMA to docetaxel, we would improve clinical outcomes for this poor prognosis patient population while having minimal impact on toxicity.

So this is the study design. Patients with metastatic prostate adenocarcinoma who'd been diagnosed within the last 12 weeks and had no more than four weeks of ADT had to have both a PSMA PET and FDG PET to be eligible.

On PSMA PET, patients had to have high disease volume and high tumor uptake—that's an SUVmax of at least 15 in at least one lesion—and no major discordant disease on FDG PET. Major discordance was defined as FDG-positive disease with minimal PSMA expression in more than five lesions or more than 50% of total tumor volume. Eligible patients were randomized one-to-one to either the control arm, which was docetaxel alone (six cycles at 75 milligrams per meter squared, the standard dose), or the experimental arm, which was two cycles of lutetium-PSMA followed by the six cycles of docetaxel. So it was actually sequential rather than concurrent treatment. Of course, patients in both arms got continuous ADT. The primary endpoint was undetectable PSA at 48 weeks, which was defined as a PSA of less than or equal to 0.2 nanograms per milliliter.

There were multiple key secondary endpoints, including PSA progression-free survival, freedom from castration resistance, radiographic progression-free survival, overall survival, quality of life and pain, and adverse events.

These are the patient baseline characteristics. They were matched between the treatment arms. But the most important thing to note here is that a majority of patients in both arms had multiple poor prognosis features: high T-stage, high grade group, and high-volume disease by conventional imaging.

These are the study results. The primary endpoint of the study was clearly met: the undetectable PSA rate at 48 weeks in the lutetium-PSMA plus docetaxel arm was 41%, versus 16% in the docetaxel-only arm—a 25% absolute difference. Odds ratio of 3.88 and a significant p-value of 0.002. We also looked at undetectable PSA rates at any time point, and this also favored the experimental arm: lutetium-PSMA plus docetaxel was 51%, versus 32% for docetaxel. Odds ratio of 2.14, significant p-value of 0.042. Interestingly, at the early time point of week 12, however, there was no difference between the treatment arms.

There were also multiple secondary endpoints that favored the experimental arm. Here are the Kaplan-Meier curves on the left for PSA progression-free survival and on the right for freedom from castration resistance. You can see that the red line, which is lutetium-PSMA plus docetaxel, versus the blue line, docetaxel, shows a significant improvement in both PSA progression-free survival and freedom from castration resistance for the experimental arm in both cases, hazard ratio 0.60, and p-values of 0.039 and 0.033, respectively.

Median radiographic progression-free survival is shown here on the left, and overall survival on the right. Again, you can see that the median radiographic progression-free survival favors the lutetium-PSMA plus docetaxel arm. Hazard ratio of 0.58—so even lower than the PSA progression-free survival and freedom from castration resistance—but in this case, the p-value did not meet the threshold for significance, with a p-value of 0.067.

Overall survival data were immature: 21% event rate at the data cutoff. You can see the median wasn't reached in either arm. Interestingly, a hazard ratio of 0.83 still favored the experimental arm, but clearly, this is not a significant result.

Quality of life and pain were similar. You can see here for the FACT-P trial outcome index on the left and BPI score for worst pain in 24 hours on the right. There was no difference at any time point in the first 48 weeks on study for the lutetium-PSMA plus docetaxel arm in red versus the docetaxel-only arm in blue.

Likewise, the adverse event profile was also similar between the treatment arms, which was reassuring that the lutetium-PSMA did not enhance toxicity overall. You can see, for example, Grade 3-4 toxicity: any treatment-related adverse event was similar between the treatment arms—29% for lutetium-PSMA plus docetaxel versus 27% for docetaxel alone. Individual treatment-related adverse events were also very similar between the treatment arms, with the exception, as you'd expect, of dry mouth, which was 37% Grade 1-2 with no Grade 3-4 events in the lutetium-PSMA arm, and no events in the docetaxel-only arm.

In conclusion, the significance of this study is that this is the first randomized trial in mHSPC to show the benefit of adding lutetium-PSMA to standard-of-care management in this patient population with de novo high-volume mHSPC. The lutetium-PSMA followed by docetaxel significantly improved the primary endpoint of undetectable PSA at 48 weeks. It also improved multiple secondary endpoints, with no increase in overall toxicity. Collectively, these data indicate that lutetium-PSMA has a potential role in the therapeutic management of mHSPC. We now await the results of the Phase III PSMAddition trial sponsored by Novartis, which will further inform the utility of lutetium-PSMA in mHSPC. If this is positive, I think it will help to change the standard of care for mHSPC.

Neeraj Agarwal: Thank you very much, Arun. That was a fantastic presentation replicating your presentation at the ESMO meeting. Congratulations on these exciting data.

Just two quick questions for the audience. Number one, I'd like to highlight that there were two cycles of lutetium-PSMA—two doses of lutetium-PSMA were added to six cycles of docetaxel. What we saw was significant and clinically meaningful improvements in outcomes, such as PSA responses, radiographic progression, delay in radiographic progression, without compromising quality of life, and without really causing any excessive side effects, which is remarkable. So please confirm, there were two doses of lutetium and not six doses of lutetium.

Arun Azad: Yeah, that's right, Neeraj, thank you. It was two cycles. The reason we did that was a couple of reasons. One was that we did not want to delay—because we gave sequential rather than concurrent treatment in the experimental arm—we did not want to delay the docetaxel by giving further cycles and pushing the docetaxel out beyond three months. With the two cycles, we obviously delayed the docetaxel starting three months because the lutetium-PSMA was given every six weeks. So that was the first consideration.

The second consideration was, as I said, this was an investigator-led trial. It was funded primarily through the Movember Foundation and an Australian government funding scheme called the Medical Research Future Fund. We also had some funding from the U.S. Department of Defense. Every extra cycle of lutetium becomes expensive, and we had a tight grant budget. So that was also a pragmatic decision.

I think the thing that I would say is that for de novo high-volume disease with mHSPC, it almost now, in retrospect, feels like two cycles was less than we would otherwise have given maybe if we were planning the study now. I think for de novo high-volume disease, potentially we undertreated these patients in some respect, and we've still got very good results, which I think shows you how potent lutetium-PSMA can be in this population. But I do wonder now if we'd given four cycles, for example, what might've happened.

It's interesting that the PSMAddition trial that I alluded to, which we're all very familiar with, is giving six cycles. I think for these patients with high-volume disease, that's very attractive. One of the things we can discuss is whether in patients with low-volume disease, who are also included in the PSMAddition trial, whether six cycles is overtreatment of some of those patients. But certainly for the patients that we recruited to this study, in retrospect, two cycles feels like maybe a little bit less than we would use if we were doing the study now. But the fact that we saw such positive results, I think, is really encouraging that this treatment's very active in this setting.

Neeraj Agarwal: Absolutely. Patients seem to have benefited significantly, even with two cycles of lutetium-PSMA. The second question is, which is frequently encountered in clinical practice, the dryness of the mouth. So what is your experience about dryness of the mouth? Does it go away as you finish the treatment with lutetium?

Arun Azad: Yeah, it's a great question, Neeraj. I mean, I think the dry mouth typically—so it's very rare with lutetium that you see more than Grade 1 or 2 dry mouth. Grade 3 dry mouth is very bad; it means that you actually need to be in hospital and get intravenous fluids and things. So really that's very significant. Even Grade 2 dryness of mouth can definitely affect patient's quality of life. I think in this study with only two cycles, nearly all of the cases of dry mouth we saw were Grade 1, and you saw the quality of life data was not different between the treatment arms. So lutetium didn't worsen that. There is a small percentage of patients when you give six cycles of lutetium who will have persistent dry mouth well beyond the completion of the treatment. It's usually no worse than Grade 1, and it's not disabling in the patient's care need, but it does sometimes have some ongoing effects, particularly when you have had that full six-cycle course.

Neeraj Agarwal: Does that dry mouth continue to get better with time?

Arun Azad: It does, typically. It does typically, but there are some patients who still will report some dryness of mouth even 6 to 12 months later. But it typically does improve after you finish treatment and then gradually continues to improve. In most cases, it does resolve. In a minority of patients, it persists, but usually to a very mild degree, typically.

Neeraj Agarwal: Very good. Thank you very much. So what do you see going forward? How do these data affect how we are going to treat our patients with prostate cancer, with metastatic newly diagnosed prostate cancer?

Arun Azad: Yeah. Well, we are always thinking about those questions, aren't we? I mean, this study ran from May 2020 through to April 2023. When we started the study, ADT plus docetaxel was a reasonable standard of care, was a very much accepted standard of care for de novo high-volume mHSPC. We didn't have access at that stage in Australia—we didn't have reimbursement—for the AR pathway inhibitors, the ARPI drugs. But of course, those drugs are now the standard of care for mHSPC, and in this de novo high-volume mHSPC patient, we know potentially even in combination with docetaxel as triplet therapy.

So I think that going forward, we need to see data that incorporates lutetium-PSMA with the current standard of care. Of course, it's a good thing that during this trial the standard of care has changed; that means we're making progress. That's fantastic news for our patients.

So now we really need to see the results of the PSMAddition trial. I think the fact that we've seen—which obviously has ARPI drugs plus ADT as the backbone in the control arm—and I think the fact that we've seen such good data, encouraging data, with just two cycles of lutetium-PSMA in this worst prognosis population of mHSPC patients, de novo high-volume, I think that makes me very encouraged that we can see even better results in a trial like PSMAddition with the use of six cycles. So we really hope that that study's positive, and then that will help to change standard of care for mHSPC patients who've got high PSMA expression on PET scan.

Neeraj Agarwal: Absolutely. And regarding the patient selection, assuming we have multiple therapeutic options, you are involved in multiple other trials in metastatic hormone-sensitive prostate cancer. In your trial, you included patients based on high PSMA uptake on the PSMA PET scan, and they had to have negative FDG scan for any prominent FDG-positive disease, to keep it simple. How do you think this selection criteria should apply moving forward to patients, assuming lutetium-PSMA is approved for patients with metastatic hormone-sensitive prostate cancer?

Arun Azad: Yeah, it's a great question, Neeraj. I mean, I think first of all, the FDG PET—we didn't see a lot of patients who were discordant with FDG PET. One of the things that we presented last week was that 22% of patients in our study were actually ineligible based on PET scan. It was usually due to low PSMA expression, and that was caused by the patients had up to four weeks of ADT. So even just with ADT alone, you can get sometimes rapid tumor death and downregulation of PSMA signal accordingly. So I think that, look, the PSMAddition trial and other trials don't use FDG PET. That's more of an Australian thing. I think with PSMAddition, they're using PSMA uptake greater than the liver, which has an SUVmax of between five to seven. So I think that's a reasonable threshold; that's what's been used in other studies.

The question will be whether ADT plus an ARPI will actually downregulate PSMA signal quite quickly, and patients may not actually have—after a couple of doses of lutetium-PSMA, especially when they have low-volume disease—may have nothing left to target. So I do wonder whether the best results in PSMAddition are going to be in patients who've got higher PSMA expression and maybe even high-volume disease. They may actually be the ones who derive the most benefit from lutetium-PSMA, and there may be actually less benefit in the patients with low-volume disease.

Ultimately, I think we need to see what the data from that trial show and then to see whether there's any particular cut point in the PSMA SUVmax or SUVmean that might help us define a patient who responds exceptionally well to this treatment. You're right; we are seeing more and more therapies available in this setting, mHSPC. ADT plus ARPI is obviously a great backbone. We have PARP inhibitor trials, which may be positive for patients with HRR alterations. We have studies with AKT inhibitors in PTEN-null patients.

So there's, I think, a lot more treatments coming. I think that in five years' time, it's quite possible we'll have a much more personalized approach to managing mHSPC, and hopefully lutetium-PSMA for patients with high PSMA expression will be part of that.

Neeraj Agarwal: Thank you for this fantastic presentation. Congratulations on your recent ESMO presentation. These are exciting data, and I'm really hoping that we have a positive PSMAddition trial in the near future, which will help personalize medicine and allow our patients to live longer without compromising quality of life. Any final conclusions before we leave?

Arun Azad: No. I just wanted to highlight that, again, thank our funding partners for supporting UpFrontPSMA—the Movember Foundation, Australian government, and U.S. Department of Defense—and also just thank all the patients, families, and caregivers, all the site investigators and staff. And then particularly, some of my colleagues at Peter Mac who helped make this happen, particularly Michael Hofman, who, as you well know, Neeraj, and the audience will know, has really spearheaded the development of lutetium-PSMA in prospective trials, and couldn't have done this trial without him and our fantastic team at Peter Mac. So thank you to all of those people.

Neeraj Agarwal: Thank you very much for taking the time to join us today, Arun.

Arun Azad: A pleasure. Thanks, Neeraj.