Optimizing the Role of Hormonal Therapy in the Care of Patients with Prostate Cancer — Professor Karim Fizazi, MD, PhD

PROF FIZAZI: Good morning, good afternoon, good evening, everybody. I’m Karim Fizazi, medical oncologist from Institut Gustave Roussy here in France, also University of Paris Saclay, and I’m delighted to discuss with you today recent data about advanced prostate cancer that we have selected.

So to make it easy, I decided simply to follow the natural history of the disease moving from localized disease, obviously at high risk for relapse and then biochemical failures, metastatic hormone-sensitive disease and mCRPC will be covered also.

So let’s start with localized disease, patients with typically high Gleason score, T3 disease or a high PSA value. One paper we just saw out there signalizes if you will, from the RADICALS Phase III trial that was also published in Annals of Oncology last year. And this is a quite large, randomized Phase III trial looking at 2 populations of patients. And actually this seems to be kind of the drawback from this trial, because it’s a mix of patients who just had a prostatectomy and they’re in, if you will, in an adjuvant setting. So if there is bad news on the prostatectomy specimen, high Gleason score, pT3 disease, something like that, but really the PSA is undetectable, so you’re treating a risk in this setting.

And the other part of the population that was enrolled in RADICALS is actually that of patients who already had a relapse, a PSA relapse, so biochemical relapse, with no detectable metastasis. So 40% adjuvant, 60% salvage, 500 men plus or minus in total. The question is whether we should use radiation therapy alone, radiation therapy with a short course of androgen deprivation therapy or radiation therapy plus ADT for 2 years. If you take the trial as a whole, there’s simply no difference between these 3 arms. And this is true in terms of metastasis-free survival and also in terms of overall survival. So you can make your life easy if want and you can use radiation therapy as your standard treatment.

But having said that, if you’re really considering patients who are randomized between ADT 6 months and ADT 2 years, there’s actually a difference favoring of a longer duration of ADT in terms of metastasis-free survival. And I’m saying that because in this trial, because this was a quite well trial, welldesigned, you had the opportunity to randomize your patients between the 2 first arms, the 2 last arms or everything. And of course, if you’re seeing a patient at low risk you may consider randomizing him for radiation alone for example, versus the same plus ADT for 6 months, but not necessarily ADT for 2 years. On the other hand, if you’re seeing a patient’s at truly high risk and your goal is already to use ADT, you will select this gentleman only for ADT and you will compare 6 months versus 2 years. So if you’re facing a man at low risk, probably it makes sense to use radiation therapy alone as your salvage treatment mainly. Now, if your patient has high risk, high Gleason score, rapidly rising PSA, something bad, then you may go for 2 years of ADT, not 6 months because again RADICALS suggests that 2 years is associated with a shorter risk of metastasis or death.

A second trial was also reported in The Journal of Urology, and this is looking at apalutamide for patients with high-risk localized disease after radical prostatectomy again. But again, these patients have an undetectable PSA, this is a purer population of patients just right after prostatectomy was performed. Again, good news on the PSA, it’s undetectable, but bad news on the pathology specimen, you have, say, a high Gleason score or T3, pT3 disease. So there’s no comparison in this basic trial and the primary endpoint was to look at time to biochemical recurrence, where you can see that actually there is good news. If you’re using a prostatectomy the PSA is undetectable and if you’re using an adjuvant hormonal agent such as apalutamide with or without ADT, basically in the short-term at least, 2 to 3 years, you don’t see any recurrence. So that’s great but it’s not of course a confirmation or demonstration that indeed these patients need any form of AR, androgen receptor targeting.

And actually very recently at ASCO GU we just saw the readout in the long-term of a randomized Phase III trial that we actually conducted here in France randomizing ADT yes or no in these patients with undetectable PSA, post-prostatectomy and poor risk features on the prostatectomy specimen, and there’s actually no benefit from early intervention in these patients. And this is true regardless of the endpoint you’re looking at, biochemical failure, metastasis-free survival and of course overall survival. So probably we should just watch most of these patients when they have undetectable PSA. Or we need to invent a better biomarker that can help us select the few of these patients who don’t do well if you don’t intervene immediately.

The second situation I’d like to comment on is that of a man with biochemical failure post-local treatment. So as we all know probably, this is a very heterogeneous situation. We know the natural history of this situation. It’s mostly predicted by the kinetic of PSA, so PSA doubling time, and by the Gleason score as assessed on the initial biopsies or the prostatectomy specimen if a prostatectomy was performed. But actually there’s a game-changer, which is PSMA PET, which is more and more telling us wherever disease is located, is that a local relapse, is that already metastatic disease or both, and probably we will need to integrate PSMA PET in the decision making in this particular scenario.

But most trials we have at the moment were conducted at times when PSMA PET was not available. And this is what I’m going to show you in this recent publications. So for example, this is PRESTO. PRESTO was a Phase III randomized trial looking at androgen-targeting agents, so ADT, or combined with AR pathway inhibitor, which is apalutamide here, in these patients with high-risk biochemical relapses. And as you can see, 500 men were randomized. They had a PSA doubling time of less than 9 months. They had a BCR post-radical prostatectomy and PSA progression-free survival was actually improved significantly favoring the apalutamide arms. But at the end of the day, this is PSA progression-free survival and we probably want stronger endpoint to make a given treatment ready for prime time.

This is actually what we had just a year before with EMBARK, which actually first read out at AUA 2023, so almost 2 years ago. And actually this was really the first trial showing that a meaningful primary endpoint of metastasis-free survival could be significantly improved when enzalutamide is being used. And this was actually true either using enzalutamide in combination with ADT as compared to ADT alone, what you can see here on the screen, but also when enzalutamide single agent was used and compared versus ADT alone. And this was an intermittent strategy of treatment, which is important to remember. To be fair with the data, the benefit we’re seeing with enzalutamide alone is probably not as high as the one we’re seeing with ADT combined with enzalutamide. So this is also important to remember. Also, you may think that most of the toxicity comes from the ADT, but enzalutamide alone also has toxicity, including cognitive impairments due to the brain barrier penetration but also gynecomastia, which can be very annoying in these patients and that is not that easy to prevent so important to know.

So I took my time on EMBARK, even if this was shown 2 years ago. And this is because we’re seeing now subanalyses of EMBARK. And this is now what I’m going to comment about. For example, Dr Freedland and colleagues reported subanalyses of a trial looking at sexual activity in these patients. And of course you may think this is very important from a patient perspective who are just developing biochemical relapse to try to keep their sexual activity as good as possible.

So let’s review briefly the data. Actually, it’s true that if you’re using enzalutamide alone, the time to deterioration in interest in sex is better with enzalutamide alone. But the magnitude of a benefit is not fantastically better. This is, if you like to see medians, it’s 8.5 months versus 5.6 months. So basically you’re gaining 3 months before your sexual activity really deteriorates significantly. So it’s a 30% reduction in the risk. And similar findings were also reported for extent of sexual activity, satisfaction with sex life, which is 11 months versus 5 months, erectile function approximately 5 months versus approximately 3 months. So again, it is better with enzalutamide alone as compared to androgen deprivation, but it’s not fantastically better. So we need to communicate this information to patients before we start treatment, either in enzalutamide alone, ADT, which probably should not any longer be used in this setting, at least in my opinion, or ADT plus enzalutamide, which actually do not protect sexual life.

Also in the trial in EMBARK we saw important data, I think, subanalyses, looking at age. And this is becoming a very serious thing because of course treating patients in the elderly is not easy. And we may actually harm patients with side effects in the elderly but also they may not necessarily get the same benefit that younger patients derive from many treatments we’re using in oncology.

But let’s review first the data we have in EMBARK. Here, enzalutamide with or without leuprolide, by the way, was tested versus ADT alone in patients with young age versus in the elderly. To the left-hand side of the slide you’re seeing enzalutamide combination with ADT versus ADT alone. ADT is the yellowish curve while enzalutamide in combination is the blue curve. And as you can see, you see 4 curves to the left-hand side, which are these subgroup of patients by age. And as you can see, the benefit is being seen across the board for patients regardless of whether they are young or old, which I think is very reassuring and very interesting to us. To the right-hand side, enzalutamide alone in red, is being compared versus ADT alone in yellow. Again, 4 curves, because you have 2 curves according to the age. And as you can see again, enzalutamide appears to be the winner versus ADT alone, and this is true in younger men but also in older men, which I think is very reassuring for a practice.

We just saw data at ASCO GU, looking at not only data of lutamide, such as enzalutamide, darolutamide, apalutamide, but also those about abiraterone. And it actually appears that abiraterone in more advanced stages does not necessarily improve outcomes, especially overall survival, in the elderly, probably because we are harming these patients from a cardiovascular standpoint.

But let’s review first another trial in patients with biochemical failure. This is probably a more modern design. This is the ARASTEP Phase III trial looking at the role of darolutamide. This is a scenario, probably more contemporaneous when you see a patient with biochemical failure, PSA is rising fast, so that’s not good news, you do a PSMA PET, and out of a sudden you realize that there are a few spots. So this is typically oligometastatic disease that we’re now seeing with PSMA PET. So it’s a brand-new situation, somewhere in between the old-fashioned biochemical failure with high risk, similar to what I just spoke about for EMBARK, but also, on the other hand, somewhere below the oligometastatic disease, that bone scan or a CT scan would be able to detect.

So how best to treat these men? We don’t know. We don’t really know. So pragmatic view is to use stereotactic radiation therapy targeting this oligometastasis progression, use also systemic treatment because this is already systemic disease and dissemination is obvious by PSMA PET, so ADT support of treatment. But the question is whether we should still intensify systemic treatment with an AR pathway inhibitor, here darolutamide, in this scenario.

So actually I can share that with you. There was quite intense discussion and debate within the steering committee as to whether the control arm should be short-term or long-term ADT, and we finally agreed on 2 years. I think this is a pragmatic decision. There is more and more data showing that 6 months may not be enough, but on the other hand, lifelong treatment with ADT is probably just too long and we want some intermittent treatment for these patients with metastatic relapse post-local treatment. So this is why the control arm in ARASTEP consists of 2 years of ADT plus stereotactic radiation therapy, while the experimental arm is the same plus darolutamide. And the trial is currently enrolling very nicely, so we’ll see the data.

Let me move now to metastatic castration-sensitive prostate cancer. We just saw data at ESMO from an important Phase III trial, which is the first one looking at the role of darolutamide with ADT alone in these patients with metastatic hormone-sensitive disease. You may say, but we already know that an ARPI is needed in this situation, which is very true. But unfortunately, this is not necessarily available in many countries. And of course we know that, since 2017, thanks to LATITUDE, STAMPEDE, ARCHES, ENZAMET, all these trials showed very meaningful overall survival PFS benefit. But again, as I said, in many countries, these drugs are not reimbursed, not approved, not accessible to many patients. So this is why this trial was designed and conducted in these countries where ADT remained the standard of care for patients with metastatic disease. So they were randomized to receive ADT alone or combined with darolutamide 6 mg twice a day. And as you can see to the right-hand side of the slide, clearly radiographic progression-free survival is significantly improved in the combination arm as was, of course, expected based on previous trial using the same family of agents.

Now, regarding overall survival, the jury is out as I’m speaking, and this is because the trial was really utilized very early because the rPFS was the primary endpoint. You can see that actually the follow-up is more a year and a half, 2 years, so most patients were alive when the trial was first analyzed. We will need a longer follow-up. Probably in 2 years’ time we should have data about overall survival. But I suspect that this will be also improved.

So I think this is important, not only for the populations who were treated in the countries where ARPIs are not available, but also for other countries such as the US or western Europe, where we have quite broad access now to ARPIs. But I’m saying that because darolutamide is very safe and this was also confirmed in the trial. This is really a drug that doesn’t add much of toxicity when added to androgen deprivation therapy. So to be honest with you, if approved, I would be quite keen to use darolutamide in many patients just because the toxicity profile is so favorable, and this is obviously true in frail patients.

Staying with metastatic castration-sensitive prostate cancer, we also show a subanalysis of the ARCHES Phase III trial, which is testing randomly enzalutamide, which actually established a role of enzalutamide in this setting together with the ENZAMET Phase III trial. So this subanalysis looked at patients according to age, lower than 75 or more than 75 years. And as you can see to the right-hand side, the benefit is being seen across the board in all these patients, or at least independently of the age, which again is so reassuring because an important proportion of all of patients are actually in the elderly.

And as I said before briefly we just saw at ASCO GU data from a large meta-analysis conducted from academia, looking at the benefit of AR pathway inhibitors in the setting of metastatic hormone-sensitive disease by both PFS and overall survival, but also looking at subgroups depending on whether the ARPI is targeting the androgen receptor, the lutamides, or whether it’s targeting hormones with abiraterone with CYP17 inhibitors. And as you can see, I think this is very important for a practice. It appears that, on the one hand, lutamide indeed prolonged life in the elderly, but not abiraterone, which again reflects part of a toxicity we’re seeing from a cardiovascular standpoint, in the elderly with abiraterone acetate. So I mean to me, this is very helpful for my practice. And when I’m seeing a patient, typically older than 75-year-old, I’m now trying to favor a lutamide and not abiraterone anymore if I can choose, and of course if there is no contraindication, while in younger patients I feel very comfortable using either abiraterone or a lutamide agent given that the efficacy is very similar, and then abiraterone may have an advantage because it’s a generic drug and also quite well-tolerated in younger patients.

Now another analysis was performed from the HERO Phase III trial, which is looking at relugolix. You might remember that relugolix is an oral agent, the first one, which is preventing the making of testosterone by being an antagonist of GnRH as opposed to leuprolide, which is an agonist. So testosterone recovery was assessed in the trial in patients who had stopped drug. And as expected, given the mechanism of action, we see more difference in recovery of testosterone favoring relugolix. And indeed, testosterone recovers very rapidly when the drug is discontinued, while with leuprolide this is a much longer time to recovery and often you have to wait for years. So that is obviously a very important finding, because in some patients you’re actually keen to go for intermittent treatment and you want your patient, or the patient wants a testosterone recovery. So in those situations an antagonist is the way to go, while in some other patients you actually see the opposite. You really want the testosterone to be suppressed as long as you can. And in these situations you may decide for an agonist.

Finally we have data to report from ARASENS regarding the effect of darolutamide against PSA as assessed at 6 to 8 months after the start of systemic treatment in patients who have metastatic hormone-sensitive disease. And again and again we’re seeing that PSA is a damn good prognostic factor in these patients with metastatic disease when assessed, again as I said, approximately 6 months after the beginning of the systemic treatment, very strong evidence looking at very low PSA value as the target for treatment. This was, of course, achieved more frequently in the darolutamide arm, and regardless of volume, high volume, or low volume, we do see that low PSA is a good thing. So this is really a target for treatment and actually this is now getting more and more potential time for further intervention or actually potentially discontinuation or lowering at least the burden of treatment in patients responding well.

So you might actually envision a new generation of trials where, in good responders, you might actually say, well maybe I should lower the burden of treatment, but of course we need to randomize data to make sure that this is safe, while on the other hand, for patients not responding well, so those with still detectable PSA at 6 to 8 months, this might be a good time to intervene if, of course, we have treatment to do that earlier and try to prevent the onset of progression and death. And actually these trials are just starting as I’m speaking, using both strategies, de-escalation and intensification.

Probably even, I think, more original is this final paper, which is also looking at this concept of response being assessed by PSA at 6 months’ time. But our colleagues actually looked at 2 different thresholds, 1 is the classical lower than 0.2 ng/mL threshold of PSA, and they confirmed, as I just showed before, that indeed patients who reach this threshold do better than those who have a PSA greater than 0.2. Okay, this is confirmation. But again, as I said, more original is this second analysis. They actually looked at whether a PSA of 0 is better or not as compared to in between 0 and 0.2, so very low values. And there could show that indeed a PSA of 0 is even better. So this is, again, the real target of overall treatment, is trying to achieve as much PSA 0 values as we can with all our existing treatment, and the next-to-come treatments. So that, I think, is very original and important for further treatment and development in trials.

Finally, I won’t have data to show because we are not in the public domain, but we have a press release about targeting Akt in patients with metastatic hormone-sensitive disease. And just to refresh your memory, I’m showing this cartoon, to show you that approximately 20 to 25% of patients have a loss of PTEN in their cancer. This is actually associated with aggressivity of the cancer. And biologically speaking, it actually stimulates the Akt/PI3 kinase pathway in parallel to the androgen receptor pathway. So if what I’m showing here on the screen is true and this is what the lab predicts, in these patients we should actually target both the Akt pathway in parallel to the AR.

And actually this was shown, I think very elegantly in a previous randomized Phase II trial, combining abiraterone with or without ipatasertib, an Akt inhibitor. And as you can see to the left-hand side, in patients with PTEN loss, you do see benefit from the combination, while for patients without PTEN loss you don’t see much benefit. And what was actually shown with 400 mg dosing was confirmed with 200 mg dosing. In patients with PTEN loss, the dual combination is a way forward, while patients without PTEN loss it just doesn’t work.

So I’m reminding this data for you because we just heard from a press release that the CAPItello-281 Phase III trial is positive. And this is a trial looking at this exact same concept in metastatic hormone-sensitive disease, and it combines abiraterone with or without capivasertib, which is also an Akt inhibitor actually approved for patients with breast cancer, and the primary endpoint of radiographic progression-free survival is being said to be significantly improved, which is great. So we just need now to see the data in the public domain, so very likely in soon-to-come congress, and of course it will be great to discuss the data and see whether the magnitude of the benefit is sufficiently important to justify use and whether this comes or not together with secondary endpoints. And this is actually the press release that just came out a couple of months ago. So this is it, and I thank you very much for your kind attention.

Other Available and Emerging Therapeutic Approaches — Emmanuel S Antonarakis, MD

DR ANTONARAKIS: Hello, my name is Emmanuel Antonarakis and today I'll be reviewing some of the key papers and abstracts from last year, 2024, in the Year in Review. I am Professor of Oncology at the University of Minnesota at the Masonic Cancer Center.

So first, an abstract by Dr Fred Saad: Efficacy of olaparib plus abiraterone versus placebo plus abiraterone in patients with metastatic CRPC with a germline versus a somatic BRCA mutation. This was a subset analysis of the PROpel trial. Just to remind the audience and to set the scene, the PROpel trial was a Phase III study in first-line metastatic CRPC. Patients were not allowed to have previously received abiraterone. They had to have an ECOG status of 0 or 1. And this was the study that looked at the combination of PARP inhibitor olaparib plus abiraterone in the first-line setting versus abiraterone alone with a placebo. This was a biomarker unselected study, which then had some post hoc analyses in the homologous recombination mutated patients and in the BRCA1, BRCA2 mutated patients. As you might recall, this trial led to the FDA approval of the combination of olaparib plus abiraterone but only for patients with somatic or germline BRCA1 and BRCA2 mutations and did not lead in the US to an unselected all-comer approval in the homologous recombination unknown or negative patients.

So the issue that this abstract wanted to answer was, is there a prognostic difference? And is there a difference in the relative benefit of the combination of olaparib plus abiraterone according to whether the BRCA1 or 2 mutation was germline versus somatic only? And the key conclusion from this trial was that the combination of olaparib plus abiraterone seemed to benefit patients both who had a germline mutation as well as those who had a somatic mutation. The 2 curves on the left show progression-free survival for germline and somatic respectively and the 2 curves on the right show overall survival for germline and somatic BRCA mutations respectively. So the magnitude of benefit was consistent in both categories.

My conclusions from this abstract are that in first-line metastatic CRPC patients with a BRCA1 or 2 mutation, both patients with germline mutations as well as patients with somatic mutations derived similar benefit from the combination of olaparib plus abiraterone relative to abiraterone alone. However, the natural history of germline BRCA mutated prostate cancers is worse than the natural history of somatic BRCA mutations.

And you can infer that by looking at the control arms of the 2 curves and you can see that those with a germline BRCA mutation have a more rapid progression and a more rapid death than patients with a somatic.

So even though the natural history of germline BRCA of prostate cancer patients is worse, the relative benefit gained from the combination of olaparib plus abiraterone is roughly of equal magnitude in both scenarios. The important thing for me here is that we must be testing all patients for both somatic, in other words tumor-derived mutations, as well as germline inherited mutations. If you stop at germline testing alone, you will miss about half of patients with BRCA mutations who only have a somatic mutation and not a germline mutation. And, of course, germline testing can be done from a saliva sample or a blood sample. Somatic testing does require tumor biopsy. This can either be a biopsy of the primary disease, in other words the prostate cancer or metastasis, and, of course, more recently we can now do circulating tumor DNA analyses for the somatic component.

The next abstract is an adjusted analysis of the MAGNITUDE Phase III study. Remember this was the study of niraparib plus abiraterone versus abiraterone alone. The primary endpoint of this trial led to the FDA approval of niraparib plus abiraterone in patients again with BRCA1 and BRCA2 positive prostate cancer in the first-line mCRPC setting. One of the things that the investigators noticed in this trial was that there appeared to be an imbalance of baseline prognostic characteristics favoring the control group here. So one of the things they wanted to do was to see whether after adjusting for those imbalances, whether the PFS and OS magnitudes of benefit, no pun intended, were preserved or even enhanced after correcting for these baseline imbalances.

This was the design of the MAGNITUDE study. It was a randomized Phase III trial again primarily first-line mCRPC patients. They were allowed to have started the abiraterone up to 4 months prior to randomization. They had to have an ECOG 0 to 1 and low pain score of up to 3 out of 10 on the BPI-SF pain scale. This study had 2 separate components, a biomarker positive component and a biomarker negative component. As you might recall, the biomarker negative component closed early due to futility showing no difference in PFS and the biomarker positive component completed enrollment and showed a radiographic progression-free survival benefit especially in patients with BRCA1 and BRCA2 mutations.

So the purpose of this abstract was to look at the unadjusted versus the adjusted analysis for PFS and OS. The adjustment method is called the IPTW, which stands for the inverse probability treatment weighting method. I don't fully understand all the details but suffice it to say that imbalances in baseline characteristics such as Gleason score and other prognostic factors could be accounted for. If you look at the lefthand side, which is the progression-free survival, you'll see an arrow showing that the unadjusted hazard ratio for PFS was 0.55 and after adjustment using this IPTW method, the hazard ratio improved to 0.67 after adjusting for the baseline imbalances. Similarly on the right side showing overall survival. The unadjusted difference in overall survival produced a hazard ratio of 0.79. And when adjusting for these baseline covariants, there was an improvement in the OS hazard ratio down to 0.65 suggesting that after adjusting for these imbalances the benefit from the combination of niraparib plus abiraterone persisted and, in fact, became greater than previously thought.

So my conclusions from this post hoc analysis of the MAGNITUDE study. First of all to remind everyone that MAGNITUDE was the randomized Phase III trial in first-line mCRPC patients initially leading to the approval of the abiraterone/niraparib combination for those that have BRCA1 and BRCA2 positive prostate cancer. There were baseline imbalances in the prognostic factors favoring the control group and thus an adjustment was done to see if those imbalances could be eliminated. After these imbalances were adjusted for, using the inverse probability treatment weighting method, the degree of PFS and OS benefit was further enhanced and amplified. However, in my humble opinion, the combination of niraparib plus abiraterone has not been widely used in the community due to a perceived lower efficacy of this PARP inhibitor ARPI combination relative to the other combinations, which are available including olaparib/abiraterone as well as talazoparib/enzalutamide.

The third paper, which I thought was quite important, was the overall survival analysis from the TALAPRO-2 trial, a Phase III study again in first-line metastatic CRPC patients comparing enzalutamide alone versus enzalutamide plus the PARP inhibitor talazoparib. The PFS was previously presented and published leading to the FDA approval of enzalutamide plus talazoparib for patients with HRR mutated metastatic CRPC. In this trial what the authors presented now for the first time was the overall survival analysis and importantly this overall survival analysis was for the overall unselected patient population including both the patients that had HRR mutation positive status as well as those that had mutation nondeficient or unknown status. Again to remind the audience, this was a randomized Phase III study of about 805 patients of first-line metastatic CRPC, ECOG performance status 0 or 1. Prior docetaxel and abiraterone were both permitted for hormone sensitive disease although that represented a minority of patients. Primary endpoint was rPFS with key secondary endpoint of OS and this is what is being presented here. In other words, the OS for the overall unselected population.

In a quite striking fashion, the overall survival for the all-comer unselected population was positive showing a hazard ratio of approximately 0.8 meaning a 20% relative reduction in the risk of death when you add talazoparib to enzalutamide as opposed to enzalutamide alone. And if you like looking at median survivals, this was about an 8.8-month improvement in the median OS from a median of 37 months in the control arm to a median of almost 46 months in the combination arm.

When you look at the subset analyses, you can see that the overall survival improvement favored almost all of the subsets shown here. I do want to point your attention to the second to last row, which is the HRR status. Patients that had HRR deficient status, in other words mutations in the HRR genes, had an even greater overall survival hazard ratio at 0.54 as opposed to those that had nondeficient or unknown HRR status where the hazard ratio for OS was diluted up to 0.87. And the last row I think is also important. The survival improvement seemed to be present whether or not the patients had received prior abiraterone or docetaxel in the hormone sensitive space. So a very consistent trend across groups.

So my conclusions from the overall survival analysis first presented at ASCO GU 2025 is that, of course, the primary endpoint of rPFS was previously met and reported. But the new information here is that in the overall unselected population, there was an overall survival advantage with the combination of enzalutamide plus talazoparib versus enzalutamide alone. And in my opinion, I believe that this combination will likely be seeking expansion of the label for the combination of talazoparib plus enzalutamide for the all-comer population. Remember at the moment this combination is restricted only to patients that have an HRR mutation but because the overall survival signal was seen in the overall unselected population, it is possible that the sponsor will seek FDA approval now for all patients not just those with HRR mutations. So that could be a significant change if it occurs.

The next abstract was presented by Maha Hussain and published in Clinical Cancer Research and this is the final analysis of the BRCAAway trial. Here's the design of the BRCAAway trial. First-line metastatic CRPC patients with a BRCA1/2 or ATM mutation. No prior enzalutamide. ECOG performance status 0 or 1. The unique aspect of this trial, even though it was a very small study of only about 60 patients, was that this trial had 3 different arms; one arm in which patients received abiraterone alone, second arm in which they received olaparib alone, and then a third arm where they received a combination of olaparib plus abiraterone. And the importance here is that in all the prior combination studies of a PARP inhibitor plus an ARPI, the control arm of all of those prior studies was the ARPI alone. There had never been a control arm of the PARP inhibitor alone as done here. And there had never been a trial with 3 arms.

The second unique aspect about this trial is that this trial had a built-in crossover design wherein patients who received abiraterone first were allowed to crossover to receive olaparib upon their first radiographic progression and conversely patients starting with olaparib alone were also able to crossover to receive abiraterone upon their first radiographic progression. So by that design, the authors were able to infer whether the sequential use of one agent followed by the second was equivalent or inferior or superior to the combination of both agents given up-front from the beginning.

This shows the primary endpoint of radiographic progression-free survival. The purple curve is the combination of abiraterone plus olaparib for those patients who got the combination up-front. The red curve are those patients that got the olaparib by itself and the blue curve, which numerically is doing the worst, are the patients that got the abiraterone alone.

Now remember I mentioned about the crossover design and the effect of the crossover can be exemplified here in this so-called swimmer plot where if you cast your eye to the left-hand side of the screen, you see the light blue bars, which are converting into red bars. So the light blue bars represent patients that started with abiraterone and then when the bar becomes red that shows the point at which the abiraterone was switched to olaparib. If you look at the middle you can see that the patients in red began with olaparib as a monotherapy and then upon progression they switched to the abiraterone in blue. And then you can see in the third on the right-hand side those were the patients that got the combination of abiraterone plus olaparib from the very beginning. And if you add up the progression-free survival 1 and the progression-free survival 2 shown in the blue and red colors respectively and you compare that to the right-hand side, the bars shown in purple, you can see even with the naked eye that the combination, the purple bars, seem to exceed even the addition of the blue bars plus the red bars again implying that the combination therapy up front might be better than sequential therapy of one agent followed by the other.

So my conclusions from BRCAAway is that this is the only trial of combined PARP inhibition in ARPI with 3 arms and 2 control arms. One control arm with abiraterone alone and the second control arm with olaparib alone both being compared against the combination. The trial had a built-in crossover design unlike the registrational Phase III trials. And the crossover design permitted patients starting with abiraterone to crossover to olaparib upon progression and also patients beginning with olaparib to crossover to abiraterone upon progression. In my humble opinion, even accounting for this crossover, the combination of olaparib plus abiraterone appears to produce a better progression-free survival than the additive sequential PFS1 plus PFS2 that might be seen with the abi to olaparib crossover or the olaparib to abi crossover. And despite the fact that this is a very small trial with only 60 patients overall, in my opinion this is the best evidence that combination therapy with PARP inhibition and ARPI might be better to sequential therapy one after another.

The next abstract is a trial design presentation of the Evo-PAR-Prostate01 study. This is a Phase III registrational study examining a new PARP inhibitor known as saruparib.

Saruparib is an oral first-in-class PARP1 selective inhibitor. What many people may not know is that there are at least 10 PARP enzymes. PARP1 is the most important and the previous generation of PARP inhibitors would inhibit PARP1, PARP2 and a few of the other enzymes and by inhibiting some of the other PARP enzymes, in addition to PARP1, that may contribute to the toxicity but may not help the efficacy component. So here we have a new drug, saruparib, previously called AZD5305, which for the first time is a PARP1 selective inhibitor. It does not inhibit PARP2 at significant concentrations. And a previous study called PETRA, which was the dose escalation study, as well as another trial called PETRANHA showed that this PARP inhibitor, saruparib, could be safely combined with the most common ARPIs including enzalutamide, abiraterone and darolutamide.

So those background studies have led to the design of this registrational trial. This is a study in metastatic hormone sensitives prostate cancer. These are patients with metastatic hormone sensitive disease, ECOG performance status 0 or 1. They are going to be tested for homologous recombination mutations at the time of screening. There are going to be 2 separate cohorts. There's going to be an HRR mutated cohort and then there's going to be a non-HRR mutated cohort. These are patients who had an adequate next-generation testing, which was evaluable but was negative for HRR mutations meaning that patients who have a test that is uninterpretable or unknown will not be permitted to enroll in this study. They have to have a documented result and that result has to either be HRR-positive or -negative. In the positive group, 550 patients will be randomized to a triplet therapy consisting of ADT plus ARPI of the physician's choice plus the PARP1 selective saruparib versus a control arm of doublet therapy consisting of ADT plus ARPI with a placebo. A very similar design will be conducted for the non-HRR mutated patients. These are patients with a known absence of an HRR mutation. This cohort is bigger, 1,250 patients. And again, they'll be randomized to triplet therapy, ADT/ARPI plus saruparib versus control arm of ADT/ARPI. Primary endpoint is radiographic progression-free survival. And they will do this in 3 subsets of patients. They will do the rPFS in the BRCA mutant patients. They will do it again in the HRR mutant overall. And then they will do it separately in the non-HRR mutant. Overall survival will be a key second endpoint. This study is currently enrolling and there are no results yet.

So my conclusions from this trial design is to remind the audience that saruparib is the first oral PARP1 selective inhibitor that spares PARP2 and other PARP enzymes from being inhibited thereby lessening, at least theoretically, the toxicity. For example, cytopenias are expected to be better with this agent. EvoPAR-01 is the first Phase III study. They are not going to be going in a metastatic CRCP population and instead they have selected the metastatic HSPC population as their first registrational study. This trial will enroll patients with both HRR mutations as well as those with known absence of HRR mutations.

And here at this point, I want to remind the audience that there are 2 other trials evaluating PARP inhibitors in metastatic hormone sensitive prostate cancer. The first is the TALAPRO-3 trial in which ADT plus ARPI plus or minus talazoparib is being investigated. And also the AMPLITUDE study, again metastatic hormone sensitive patients, with a combination of ADT/ARPI plus or minus niraparib. I also want to state very, very clearly that at this point in time there is no FDA approval of any PARP inhibitor in the metastatic hormone sensitive space even for patients with known BRCA1 and BRCA2 mutations. So these 3 trials, the EvoPAR-01, TALAPRO-3 and the AMPLITUDE will be the first trials that might suggest that PARP inhibition in the metastatic hormone sensitive space is indicated. The results are awaited for all 3 of those trials.

Now let's shift gears to talk about some radiopharmaceutical drugs. This was the abstract presented at ESMO by Silke Gillessen. This was the long-awaited PEACE-3 trial, a European trial looking at patients with first-line mCRPC who were about to embark on enzalutamide with or without the addition of Radium-223. Many of us, including myself, had sort of forgotten about 223 for a few years. It was FDA approved several years ago for patients with symptomatic bone dominant metastatic CRPC. But here this was the first trial, or one of the first large trials, to study the combination of Radium-223 with enzalutamide versus enzalutamide alone in patients with primarily first-line metastatic CRPC who had not previously received enzalutamide. Patients were asymptomatic or mildly symptomatic. They couldn't have known visceral disease. The primary endpoint of this study was rPFS with a key secondary endpoint of overall survival. Importantly after the first 119 patients were enrolled in this study and where there was a signal of increased bone fractures detected, the study was amended requiring that all patients receive a bone protecting agent such as zoledronic acid or denosumab.

The radiographic progression-free survival endpoint was met and this was very encouraging as shown on the left-hand side. But the part of this study that took me by surprise and also shocked many of the people in the audience at the ESMO meeting was the very striking and large overall survival difference shown on the right where you can see that 6 cycles of Radium-223 when added to enzalutamide improves overall survival by 31 percentage points giving a hazard ratio of 0.69. The threshold that needed to be met with respect to p-value was less than 0.0034 and as you can see there the p-value was under that. It was 0.0031. So statistically speaking this was positive for a key secondary endpoint of overall survival.

The side effects were slightly increased in the enzalutamide/Radium group with more fatigue at 5.5% Grade 3 versus 1.8% Grade 3 fatigue. Increased risk of fractures 5% versus 1%, increased anemia 4.6% versus 2.2% and increased risk of neutropenia 4.6% versus 0%. These are all Grade 3 or Grade 4 side effects.

So my conclusion from PEACE-3 is that this trial showed a statistically significant and clinically meaningful improvement not just in progression-free survival but also in overall survival when Radium-223 for 6 cycles was combined to standard enzalutamide. Conversely I want to point out, and we're going to review this in a moment, the use of lutetium-PSMA, for example, in the PSMAfore trial, did not show an overall survival advantage when used prior to docetaxel chemotherapy. We'll talk about that soon. The safety of the enzalutamide/Radium combination was quite reasonable with a small percentage point of Grade 3 fatigue, anemia, neutropenia and also weight loss. And finally if this combination is ever entertained, it should always be done so in the context of a bone-protecting agent. I should state at this point that in the US and in Europe the combination of enzalutamide plus Radium has not been approved by regulatory bodies at this point, although that may change in the future.

Now I did hint about the PSMAfore study. This was one of the most eagerly anticipated trials I would say of 2024 in all of oncology. Here we're talking about lutetium-177 PSMA-617. This was the drug that was FDA approved 2 years ago in March of 2023 in patients with third-line metastatic CRPC who had previously received an ARPI agent and a taxane chemotherapy. And in that setting this agent improved both progression-free survival and overall survival.

So the question is, if you move lutetium-PSMA-617 in the mCRPC prechemotherapy setting, patients who have not yet received chemotherapy for metastatic CRPC, will you also show the same degree of benefit? So this was the trial design. First-line mCRPC patients. The patients could not have received a taxane for metastatic CRPC. They all had to have received one prior ARPI agent but not more than one. And then they were randomized to the lutetium-PSMA-617 or an alternative ARPI switch. For example, enzalutamide in patients having received abiraterone or abiraterone in patients having received enzalutamide. The lutetium-177 was given intravenously every 6 weeks for a total of 6 doses. The dose was 7.4 GBq. Importantly, the primary endpoint here was radiographic progression-free survival and upon the confirmation of radiographic progression, patients in the control arm, the ARPI arm, were allowed to crossover and to receive lutetium-PSMA. And strikingly 84% of people in the control arm did actually crossover to receive lutetium-PSMA. And I'll get back to this in a second because this may have influenced and perhaps diluted the overall survival advantage.

So first let's focus on the top left Kaplan-Meier curve. This shows the primary endpoint of radiographic progression-free survival. This was unequivocally met as you can see with the large separation of the curves. If you look at the bottom left, overall survival not so different and, in fact, the hazard ratio for overall survival was 0.98, very, very close to 1, not statistically significant. Once again, it is possible that an overall survival effect may have been diluted because of the 84% crossover rate. Other endpoints including PSA response and objective response also favored the lutetium-PSMA group.

Side effects. We can see more dry mouth with lutetium-PSMA. We see more nausea. We see more anemia and diarrhea. But as you can see there, the Grade 3 events were relatively low and most of those side effects were Grade 1 or Grade 2.

So my conclusions from PSMAfore is that this is the first study to test lutetium-PSMA-617 in the pre-taxane mCRPC space. We saw an improvement in radiographic progression-free survival but not in overall survival, although the high degree of crossover may have influenced the lack of OS. The toxicity profile is very favorable but does include dry mouth, nausea, diarrhea and anemia. And very importantly, on March 28, 2025, approximately 2 years after the initial FDA approval of lutetium-PSMA-617, the FDA expanded the use of lutetium-PSMA-617 into the pre-taxane mCRPC setting based on the results of this trial. What this means is that a patient now who has failed or progressed after 1 single ARPI agent, for example, abiraterone or enzalutamide, who has not yet received chemotherapy and who wishes to defer or delay the use of chemotherapy, can now receive lutetium-PSMA-617 prior to failing a taxane agent. I think this will be quite a transformative change in our practice pattern moving forward.

Another interesting abstract also with lutetium-PSMA-617, which was published also in The Lancet Oncology was from Louise Emmett. And this is the overall survival of a previously reported study called the ENZA-p trial. The PFS had been previously reported and now the overall survival is mature. So this is the design of the ENZA-p trial. These were patients primarily with high-risk first-line metastatic CRPC. They could not have received chemotherapy for CRPC. They had to have a positive PSMA PET scan. They had to be eligible for enzalutamide treatment. And then they were randomized to enzalutamide alone or lutetium-PSMA-617 for a minimum of 2 doses and up to 4 doses. PSA-PFS was the primary endpoint. Radiographic PFS and OS were key secondary endpoints.

If you look at the left-hand side of this slide, you can see a clinically significant but perhaps not statistically significant radiographic progression-free survival improvement with a hazard ratio of 0.68 with the confidence interval crossing 1. But what was more striking in this trial and unexpected, at least to me, was a statistically and clinically significant improvement of overall survival when adding 2 to 4 doses of lutetium-PSMA to enzalutamide in the high-risk metastatic CRPC setting. So that was quite unexpected from my perspective.

Again the side-effect profile generally manageable but there was an increase in fatigue, nausea, dry mouth, dry eyes and some cytopenias including anemia and thrombocytopenia. Again most of those side effects were Grade 1 to Grade 2 although there was some Grade 3 anemia, small fraction of Grade 3 thrombocytopenia with the combination of lutetium plus enzalutamide compared to enzalutamide alone.

My conclusions from Enza-P are that this is the first study to show an overall survival advantage. When lutetium-PSMA was used prior to taxane chemotherapy when combined with enzalutamide, relative to enzalutamide monotherapy, the combination of lutetium plus enzalutamide improved PFS although not to a statistical degree. Also improved OS as well. There were other improvements, for example, in deterioration-free survival and time to pain and also fatigue. The side-effect profile was manageable with dry mouth, dry eyes, nausea and cytopenias being the main side effects but they were mainly Grade 1/Grade 2. But, once again, I do want to remind the audience that at this time the combination of enzalutamide plus lutetium-PSMA is not currently FDA approved. And I would say that based on the fact that this was a randomized Phase II trial, in my opinion, larger randomized Phase III international trials are needed to confirm the benefits seen here.

Another radioligand, which is similar to but different from lutetium-PSMA-617, is called lutetium-177-PNT2002. This was the SPLASH trial led by Dr Oliver Sartor. This agent is a similar molecule to the lutetium-PSMA-617. However, it has a different linker so it still targets PSMA. It still delivers lutetium-177 but the linker that links the PSMA ligand to the radioactive molecule is different than proprietary and thus it has a different name. So this trial was also a prechemotherapy metastatic CRPC study. Patients had to have received one prior ARPI agent but no chemotherapy for mCRPC. They had to have a positive PSMA PET scan, ECOG performance status 0 or 1. Taxane was allowed but only if it was delivered in the hormone sensitive setting. And then patients got this particular radioligand, PNT2002, at a dose of 6.8 GBq every 8 weeks for up to 4 cycles versus the alternative ARPI. And here the randomization was 2:1 favoring the radioligand group as opposed to 1:1. And once again a crossover was permitted in the control arm and, in fact, a large majority of patients 84.6% did crossover. rPFS was the primary endpoint and there were a number of secondary endpoints as well.

If you focus on the left-hand Kaplan-Meier curve, you will see that the primary rPFS endpoint was met although perhaps the difference in the 2 curves was a little bit more modest than what we saw with PSMAfore utilizing the lutetium-PSMA-617 molecule. If you look on the right-hand side, overall survival was not different and, in fact, the hazard ratio was higher than 1, 1.11 in fact, although the overall survival interim data is still quite immature.

If you compare the PSMAfore study with lutetium-PSMA-617 with the SPLASH trial using lutetium-PSMA2002, you can see that the hazard ratio for PFS was 0.49 in PSMAfore and 0.71 in SPLASH suggesting that perhaps the SPLASH regimen may not be as superior as the PSMAfore regimen. Similarly with overall survival, although both hazard ratios are close to 1, the hazard ratio was perhaps a bit more favorable for survival in the PSMAfore trial. And additionally PSA responses and objective responses were a little bit higher with PSMAfore compared to the SPLASH trial.

Why might that be the case? Well, I'm going to speculate on that. First of all, just to summarize here that the SPLASH study using lutetium-PSMA-PNT2002 appears to show a more moderate rPFS benefit compared to the PSMAfore trial utilizing PSMA-617. Here is my hypothesis or at least one of my hypotheses. The dose and schedule of the radioligand was different in the 2 trials. In the SPLASH study, the dose was 6.8 GBq given for up to 4 cycles. In the PSMAfore trial, the dose of the radioligand was 7.4 GBq, higher dose, given for up to 6 cycles. So the cumulative total dose of radioligand therapy that was delivered in the PSMAfore study was significantly higher than that in the SPLASH study. It is possible that a higher dose intensity that was achieved in PSMAfore relative to SPLASH might potentially explain the slightly higher efficacy with respect to PFS.

Finally, I want to remind everyone that lutetium-PSMA-PNT2002 is not currently FDA approved and it's not clear whether the sponsor will be seeking FDA approval based on these results which were, let's say, lukewarm at this time. And we cannot currently use this medication in our daily practice.

I've got 1 or 2 more important abstracts that I'll get through quickly. The first is the final overall survival analysis of the CONTACT-02 trial, a combination of cabozantinib plus atezolizumab versus novel hormone therapy switch. Here's the trial design. It was previously published. The previous publication focused on the progression-free survival primary endpoint. This updated presentation now reports the overall survival. These were patients with metastatic CRPC. They had to have a prior ARPI agent. They couldn't have received chemotherapy for metastatic CRPC and they had to have measurable disease based on a CT scan. They were randomized to receive either cabozantinib plus the PD-L1 inhibitor atezolizumab or the alternative novel hormone therapy agent. The updated presentation now reports the overall survival. Here I just want to review the progression-free survival, which shows an overall improvement in the intention-to-treat population shown on the left. And then I also want to call out the liver metastasis subset and the bone metastasis subset where you can see perhaps in the liver met subset there is a greater degree of benefit with the combination of cabo plus atezo relative to the alternative androgen receptor pathway inhibitor.

And here the new data, overall survival. The punchline is that while the overall survival in the overall intention-to-treat population was not significant with the combination of cabozantinib plus atezolizumab, what we do see in the liver subset is perhaps a hint of an overall survival benefit with a hazard ratio of 0.68 and a p-value that was equal to 0.05 so just on the cusp of statistical significance. And then also perhaps a signal also in the bone metastasis subset showing perhaps an improved overall survival with the combination of cabozantinib plus atezolizumab in that subset as well.

So my conclusions are that the CONTACT-02 study met its PFS endpoint that was previously reported. Here what we saw is that OS was not met in the unselected ITT population but in the subset with liver metastases and to a lesser degree bone metastases there did appear to be an overall survival trend once again primarily in the liver met subset. The side effects were primarily manageable and included the known side effects of cabozantinib such as hypertension, diarrhea, anemia, hand/foot syndrome and fatigue. It's important to note that in metastatic prostate cancer, neither cabozantinib nor atezolizumab are currently FDA approved in any setting even as monotherapies. And although it's possible that regulatory approval might be sought for the liver metastasis subset, that approval has not been granted yet. One open question that I have in my mind is, does the atezolizumab add anything? And if you cast your mind back about 10 years you might remember the COMET-1 and COMET-2 studies, which tested cabozantinib as a monotherapy in prostate cancer and those trials did show a PFS improvement compared to placebo. And they showed a certain proportion of objective responses in PSA responses. So in my mind, I'm not sure whether there is true synergy between cabo and atezo or whether this result may have been seen with just the cabozantinib alone.

Dr Schweizer presented an interesting compound called mevrometostat. This is an oral EZH2 inhibitor that was combined with enzalutamide. EZH2 is an epigenetic regulator that affects the chromatin states. When the chromatin are tightly wound, they prevent the expression of genes including tumor suppressor genes. When those chromatin become unwound by inhibiting EZH2, it allows several genes, including tumor suppressor genes, to be expressed. My hypothesis here was that if you inhibit EZH2 and you add an antiandrogen like enzalutamide, you will reverse secondary resistance to the enzalutamide. You will prevent lineage plasticity and the emergence of the so-called neuroendocrine state. So the trial design was patients who had received prior abiraterone and progressed. They now had metastatic CRPC. They could have received 1 prior chemotherapy regimen. And then they were randomized to enzalutamide alone in the post abiraterone setting or the combination of enzalutamide plus the oral EZH2 inhibitor now known as mevrometostat. Primary endpoint was radiographic progression-free survival. The primary endpoint was met. When mevrometostat, the EZH2 inhibitor, was combined with enzalutamide, there was an improvement in radiographic progression-free survival by about 50% with a hazard ratio of 0.51. You can think of that approximately as a doubling in PFS and you can also see a doubling in the objective response rate and a doubling in the PSA50 as well.

Side-effect profile. This agent primarily affects the gastrointestinal tract so diarrhea, anorexia, nausea and taste changes are the main side effects. Anemia was also seen, as was alopecia. Forty percent of patients had some degree of hair loss despite this not being a chemotherapy agent.

My conclusions from this randomized Phase II study, is that mevrometostat, the oral EZH2 inhibitor, enhances the efficacy of enzalutamide in the post-abiraterone mCRPC setting, producing a hazard ratio of about 0.5. Mevrometostat at a dose of 875 mg combined with food is now going to be recommended as the Phase III dose. The adverse events of this agent are primarily GI in nature, with diarrhea, nausea, taste changes being common and also some degree of alopecia. There are 2 Phase III studies that have been designed and are about to open, the MEVPRO-1, which is a postabiraterone metastatic CRPC study and the MEVPRO-2, which is a pre-abiraterone ARPI-naïve study. In both of these trials, enzalutamide plus placebo is going to be compared against enzalutamide plus mevrometostat.

And finally, I want to talk about another new agent, a CYP11A1 inhibitor, now known as opevesostat, and this is now being tested in 2 Phase III trials. Before we get to that, let’s discuss this medication. It used to be called ODM-208, was then changed to MK-5684 and is now known as opevesostat. This is an oral inhibitor of the CYP11A1 enzyme. This is an adrenal enzyme that converts cholesterol to pregnanolone. It’s the first step in the adrenal steroid synthesis pathway, as you can see on the left-hand side. When you inhibit CYP11, you’re inhibiting androgen synthesis but you’re also inhibiting glucocorticoid and mineralocorticoid synthesis. By decreasing the supply of glucocorticoids and mineralocorticoids you’re preventing those alternative steroid ligands from binding to the androgen receptor. And on the right-hand side of this diagram, you can see that there are certain mutations in the androgen receptor gene that cause other promiscuous steroids to bind and stimulate the androgen receptor. For example, glucocorticoids can stimulate the AR in the context of that L702H mutation. Progesterone can stimulate the AR in the context of the T878A. Estradiol can stimulate the 875Y.

In the Phase II study that was previously published by Dr Karim Fizazi, called CYPIDES, you can see that this agent had activity both in patients without and with AR activating mutations, but the activity was greater in those with the AR mutations as shown on the left. And because of this promising activity in the Phase II trial, there are now 2 ongoing Phase III randomized studies testing this agent, the first is called OMAHA-004. This is a pre-chemotherapy metastatic CRPC study. Patients have to have failed 1 prior ARPI. No chemotherapy is permitted except for docetaxel in the hormone-sensitive state. And then they are randomized to the oral opevesostat plus hormone replacement therapy with dexamethasone plus fludrocortisone versus the alternative novel hormone agent. At the bottom, the design is virtually identical except that, in OMAHA-003, this is a postchemotherapy trial so patients are required to have failed 1 ARPI and 1 to 2 taxanes in the CRPC setting, and once again they’re randomized to either opevesostat plus hormone replacement, adrenal replacement therapy, versus the alternative ARPI. Both of these trials are powered for both PFS and OS and they are powered for both AR mutation-positive and AR mutation-negative patients.

So my conclusion here is that opevesostat is an oral CYP11 inhibitor that suppresses production of all adrenal steroids. It has shown clinical activity in Phase II studies, primarily in patients with AR mutations but also in some patients without. The OMAHA-004 and OMAHA-003 studies are randomized trials testing opevesostat versus ARPI switch in the pre-chemotherapy and post-chemotherapy settings respectively. However, because this agent is basically a medical adrenalectomy, you need to supplement these patients with both glucocorticoids, such as dexamethasone, as well as mineralocorticoids, such as fludrocortisone.