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Rana McKay: Hello, everyone, and welcome to UroToday in our online medical education program, Beyond Androgen Blockade in New Pathways and Novel Treatments in mHSPC and mCRPC. I'm Rana McKay, and I have the honor to moderate today's discussion following a presentation by Dr. Alicia Morgans on the topic of 2023 key learnings in MCRPC treatments. Alicia, it's a pleasure to have you.

Alicia Morgans: So wonderful to be here. Thank you so much, Rana. I have the honor of presenting on key learnings in metastatic castration-resistant prostate cancer treatments for the last year to year and a half, and there have been a flurry of updates. So let's get started. So TRITON-3 is one of the studies that has been presented in the last year. This is a really interesting study looking at rucaparib in the metastatic castration-resistant prostate cancer population. As we can see here in the schema, this included patients with mCRPC, who had BRCA1, BRCA2, or ATM alterations, and had had disease progression after treatment with a prior line of androgen receptor signaling inhibitor therapy. These patients did not receive chemotherapy for mCRPC and were enrolled and randomized two to one to receive physician's choice of the alternate AR targeted agent or docetaxel, which I think is a really interesting and important difference in that randomization. Because previously, we had not seen the comparison of treatment with a PARP inhibitor versus docetaxel.

So this is really important in novel here. So patients were followed for radiographic progression of disease and, certainly, could have that optional crossover, as we see here, and were followed for PFS as a primary endpoint. And what we could see, when that data was presented and actually published in New England Journal of Medicine, as we can also see in these figures, rucaparib was compared to docetaxel. In this top left box, we can see that rucaparib in this mCRPC selected population was superior to docetaxel, in terms of radiographic progression-free survival. Hazard ratio here is 0.53. So that's a very significant benefit. If we look down in panel B, on the left, we can also see that rucaparib was superior, in terms of radiographic progression-free survival in the selected population versus the second androgen receptor pathway inhibitor. Over on the right, I think also importantly, we can see this specific subset of the ATM alteration patients. And here we can see that there's not a clear benefit to treatment with either docetaxel in the top box or the second AR pathway inhibitor, when we compare to rucaparib. These are basically overlapping lines.
So no difference really in our PFS between the PARP approach versus docetaxel or the second AR targeted agent in the ATM subgroup. This, I think, is important and really justifies what we've been saying for the last few years that perhaps those patients with BRCA1 and BRCA1 alterations are most responsive to targeting with PARP inhibitors. There may be other alterations in the HRR pathway, that are also quite responsive, but ATM probably is not one of the more responsive subgroups within this population. And this was born out in the TRITON3 data here. We also, in the last year or so, have had continued updates on those combination studies with PARP inhibitors and AR-signaling inhibitors in the first-line for metastatic castration-resistant prostate cancer. This is the schema for PROpel, which I think many of us are quite familiar with. This included patients with mCRPC.

This was an all comers patient population. They had received potentially ADT and docetaxel in the metastatic hormone sensitive setting, but they could not have had prior exposure to abiraterone. There was no screening for HRR mutation. So again, an unselected patient population, though patients after enrollment and randomization did undergo genetic testing to understand their HRR status. Patients in this setting were randomized to treatment with abiraterone, with or without olaparib, and were followed for radiographic progression-free survival primary endpoint here. And here, we can see PROpel's primary endpoint here, radiographic progression-free survival. This is from the New England Journal of Medicine Evidence paper published in 2022. We could see that separation of curves in the all comers population demonstrating that the combination of abiraterone with olaparib was superior to treatment with abiraterone alone. I would say, so importantly, that abiraterone is quite a powerful control arm in this setting.

It is standard of care. These patients had not been exposed to abiraterone previously. So to have that benefit really augmented by the addition of olaparib in an all comers population, I think, is really meaningful and actually contributed, of course, to the approval of this combination, which in Europe, actually includes an all comer population, in the US, is really fixed on the BRCA1 and BRCA2 population. As we look further, we can see the updated data here from the Lancet Oncology paper. This is the overall survival curve. This is not yet mature, but does suggest that there's a separation of curves with olaparib and abiraterone combination, showing some trend towards superiority versus abiraterone alone in this population. Again, this is not yet mature. We do need to continue to follow this. That p-value looks like it's less than 0.05 or at least reaching that. But given the spend here that we have, due to multiple testing, we are going to have to have a lower p-value than that to actually reach statistical significance. But a trend nonetheless.

So MAGNITUDE is another study I think many of us are already familiar with. This is, again, first-line mCRPC setting, and this included patients with mCRPC, who had biomarker positive disease and those who had biomarker negative disease initially. These patients could have been exposed to prior abiraterone for four months or less and could have had docetaxel in that earlier disease setting for metastatic hormone sensitive disease. Importantly here, those patients who are biomarker negative did not seem to benefit from the randomization of abiraterone, with or without niraparib. So no difference there. That cohort was actually discontinued, in terms of follow-up and enrollment for futility. But the biomarker positive population did move on, again, randomized to treatment with abiraterone, with or without niraparib. Again, just to say that abiraterone is quite a powerful control arm here, in this first-line mCRPC setting, without prior exposure to AR signaling inhibitor.

And the primary endpoint here is radiographic progression-free survival. And here, we can see this was just published this year in the Annals of Oncology, the separation of curves for patients who had BRCA1 and BRCA2 alterations, this is the radiographic progression-free survival data, demonstrating superiority of the combination of niraparib and abiraterone versus abiraterone alone. Hazard ratio here is 0.55, highly statistically significant. And if we look here at the overall survival data, this is not yet mature. We can see that there may be separation. We really can't tell at this point in time. We do need to wait for maturity of this analysis. TALAPRO-2 is another study that reported out this year. Really exciting that we see a third combination of a PARP inhibitor and an AR signaling inhibitor. This is also first-line mCRPC. Patients could have received abiraterone in that earlier setting though for metastatic castration-sensitive prostate cancer, and they could have had taxane in that setting as well.

These patients could have had HRR mutations, but did not have to. They did do testing for all comers as they came into the study, but it was an all comers follow-up, all comers in one randomization. Here, we can see patients randomized the treatment with enzalutamide, with or without talazoparib. And here, we also see that the primary endpoint is radiographic progression-free survival, consistent with all of these first-line mCRPC studies. So here, we could see the primary endpoint of radiographic progression-free survival. This was published just this year in the Lancet, by the team, and we can see that the combination of enzalutamide with talazoparib was superior, in terms of radiographic progression-free survival, versus enzalutamide alone.

And again, to emphasize, enzalutamide as a single agent is highly, highly, highly active in this first-line mCRPC setting. And here, we can see the radiographic progression-free survival for TALAPRO-2 really split out by HRR subgroup gene alteration here. On the left, we can see patients who have HRR positive alterations, so patients who have those HRR mutations and the clear separation of curves, with the benefit being very statistically significantly greater with patients being treated with enzalutamide, with talazoparib, versus enzalutamide alone.

Here the hazard ratio is 0.46, so even more pronounced than the last slide in the all comers population. For patients who did not have HRR deficient disease or who were really unknown in terms of that status, we can see, on the right, that this was a clear separation of curves, that did meet statistical significance, though this was less pronounced with a hazard ratio here of 0.70. So really looking at this by HRR status demonstrates that benefit of the combination of talazoparib and enzalutamide versus enzalutamide alone, but most pronounced in patients with HRR mutations in their cancer or germline status. So if we look at all of these combinations, there are three new combinations with approvals now in 2023 for PARP inhibitors and AR pathway inhibitor combinations in first-line metastatic CRPC. On the left, we can see olaparib and abiraterone. This was the first approved combination from the PROpel study for patients who had BRCA mutated metastatic castration-resistant prostate cancer.

In the middle, we can see the talazoparib and enzalutamide combination also approved here, but this is approved in first-line mCRPC for patients who have any of the HRR mutations and have that, again, first-line, mCRPC setting. And then, niraparib and abiraterone also approved in August. This is for a BRCA mutated mCRPC population for niraparib and abiraterone. So let's move on. So other learnings for this year, for metastatic CRC, we really, I think, are starting to pull apart our understanding and really dig and dive in to our understanding of, how do we select patients for treatment with lutetium PSMA-617. And within the VISION trial, of course, we know that patients were randomized to treatment with best supportive care or best standard of care versus best standard of care with lutetium PSMA-617. And within that population that received lutetium PSMA-617, we could see that radiographic progression-free survival was certainly superior, in the whole population actually, superior with lutetium PSMA-617, if those patients had a higher SUV mean, in their disease, on their PSMA PET.

Now, SUV mean means the average SUV over all of the lesions identified on that PET scan. And importantly, this is not something that is typically reported on a standard PET scan report. This is something that does need to be calculated separately. This is not an SUV max. And so, this is not something that we standardly get in clinical practice, but is something that, I think, we hopefully will be starting to get at some point in the future as we're trying to help select which treatment is going to be best for patients. So those patients with an SUV mean over 10 seem to have the most robust radiographic progression-free survival in this VISION trial, when treated with lutetium PSMA-617. And you can see the decline in benefit there as the SUV mean decreases from 10 all the way down to the lowest, which is less than six, but still meeting criteria for PSMA PET positivity, such that these patients could be enrolled in the trial.

So this may be something, again, that helps us to select which patients are going to be most benefiting from treatment with lutetium PSMA-617 versus patients who may use other alternative therapies, if they have some PSMA PET uptake, but it's not really meeting threshold and perhaps they may benefit from things like chemotherapy or other options. And this, I think, is still to be determined. PSMAfore is a study that randomizes patients with metastatic CRPC, who have already had progression of disease on an AR pathway inhibitor to treatment with the alternate AR pathway inhibitor or lutetium PSMA-617. Importantly, when patients reach progression, there can be crossover from that AR pathway inhibitor arm over to treatment with lutetium PSMA-617. This is something that we have all actively anticipated, because we do have a press release saying that this is a positive study for RPFS, and we expect that we will get more details on this at ESMO 2023.

Here is the press release stating that. So really exciting and something that we are looking forward to. And we also have had a press release suggesting that the study looking at cabozantinib and atezolizumab in the mCRPC setting is also a positive study, demonstrating benefit to that combination, versus the alternate AR targeted agent in this mCRPC first-line setting for patients who had had progression of disease on an AR targeting agent in the past. I think, so importantly here, cabozantinib and atezolizumab, as single agents, have not shown promise in prostate cancer. So the fact that the combination may show benefit, and we expect and hope to hear this data at an upcoming meeting in the future, is really exciting and a way for us to potentially transform agents that, as single agents, are not effective, but as combinations may provide some synergy that provides effectiveness for our patients.
So in summary, treatment of patients with mCRPC continues to evolve rapidly. This was very clear in 2023. And PARP inhibitor monotherapy is certainly still an option for our patients with HRR alterations. Importantly also, we saw new data that treatment with PARP for patients with BRCA1 and BRCA2 mutations in particular may be superior to chemotherapy. And this is a new piece of data that has been revealed with this updated rucaparib data that I showed. Combinations of PARP inhibitors with our AR pathway inhibitors are newly approved. We've got three combinations in the first-line mCRPC setting, so really exciting to move forward with that.

Importantly, PSMA PET scans are here to identify patients who may be eligible for treatment with lutetium PSMA-617, currently after progression on an AR pathway inhibitor and docetaxel, as we saw in the VISION trial. But we do expect to see some new data coming out, that may give us the opportunity to ultimately move that lutetium PSMA-617 into a pre-chemotherapy space. We are waiting for PSMAfore to be reported very soon. And novel approaches, including cabozantinib and atezolizumab will also hopefully be available in the near future. We will see data at an upcoming meeting. Thank you so much for your time.

Rana McKay: Thank you so much, Alicia, for that amazing summary of really all the top line data that's been presented over the last year at key meetings, ASCO, ESMO. So really exciting. There's been a lot of commotion around PARP inhibitor combinations in the frontline mCRPC setting. What's your biggest takeaway from that disease space and those trials?

Alicia Morgans: I agree, commotion is a great way to describe it. It's nice that we are really debating this and thinking through it as a field. And I commend us for doing that, but it is leading to a lot of confusion, I think, also, as we're trying to use this data. When I look at the data for patients who are selected to have those HRR mutations, I would absolutely agree that the combination of the PARP inhibitor plus the AR signaling inhibitor does suggest a really robust response and importantly, as I said before, against a really active control. So that's very exciting. When I do look at the unselected population, however, it does look to me like there is some potential synergy, because I wouldn't expect there to be any benefit from adding a PARP to an AR signaling inhibitor when there is no, whether it's BRCAs or something that could be incited or induced by the exposure to the PARP.

So I do think there's something there, perhaps it's because we just don't know the alterations that may exist that are responsive to PARPs in those populations that are unselected. But I do hope that we will continue to have exploratory findings come out and more analyses to help us understand whether there might be synergy that can make more patients than the ones currently included in the approvals eligible for combination. Because any patient that can benefit and really deal with the adverse events, which I think are relatively manageable, is one that I want to try to get that combination to, if possible.

Rana McKay: Wow, that's been so helpful. I know it's been tough making sense of the data, but I think you hit the nail on the head of, yeah, there's definitely a population that derives great benefit, those patients with the HRR alterations, but there's definitely a signal in those people without the HRR alterations that's worthy of further exploration. Thank you so much for that, Alicia. I think the other really exciting new treatment that's entered into the landscape is lutetium PSMA. And a lot of really exciting data about its activity and improving survival for patients, robust PSA responses. How do you think this treatment is going to end up getting layered into the advanced prostate cancer setting?

Alicia Morgans: Another great question. So I think that there will be strong interest in incorporating lutetium PSMA-617 into earlier and earlier lines of therapy, as that is possible. And I think the first area where this may be possible and covered by expanded approval will be the pre-chemo space. But there is investigation currently ongoing, looking at this in even earlier settings, including metastatic castration-sensitive disease and earlier, though the studies that are much, much earlier are not registration trials. So it is possible that we are going to find that this is going to be something we use very early on for some of our patients.

I think, as we do that, we're going to have to use things, like SUV mean, to ensure that we're treating patients with the best therapy for them or at least do our best in helping to support that decision making. Because just having a positive PSMA PET does not necessarily mean that lutetium PSMA-617 is the best treatment. It just means that it is a potential option. So although there's excitement around this agent, I think it's important for us to think carefully with our patients to really consider the bone marrow and other toxicities that we have, to just be aware of, and then, make the right choice for each individual.

Rana McKay: Thank you so much for joining us today, Alicia. It's really been a pleasure. Please tap into our masterclass, and you can watch Alicia again go through her highlights of 2023.

Alicia Morgans: Thank you.