Optimizing the Role of Hormonal Therapy in the Care of Patients with Prostate Cancer — Andrew J Armstrong, MD, ScM

DR ARMSTRONG: I’m Andrew Armstrong. I’m a medical oncologist at Duke University and the Duke Cancer Institute Center for Prostate and Urologic Cancers. It’s an honor to be with you to talk about the year in review, particularly with a focus on some of the changing landscape of hormonal therapy, some of the innovations that are being developed in hormonal therapy and some of the patient-centric endpoints that we’re using to make treatment decisions in clinic.

I’d like to start off by just highlighting a paper that we published 2 weeks ago in the Journal of Clinical Oncology. This is called Prostate Cancer Working Group 4. For those of you who are conducting clinical trials in prostate cancer this is an every-10-year update where we update guidance from eligibility endpoints, patient-reported outcomes, how to define response and progression in this disease. It tends to be one of the most highly cited papers over a 10-year period. Prostate Cancer Working Group 3 was 10 years ago.

Going forward one of the recommendations is around terminology and avoiding the term castration-sensitive or -resistant disease. That’s not really a patient-centric term that patients prefer to use themselves or doctors when they’re communicating what this hormone disease state is, and so we’ve used — or coined the term androgen pathway modulation. As you’ll see from some of my future slides, we’re now starting to see patients being treated with AR inhibitors without testosterone-lowering therapy, or ADT, and so what do you call a patient when their testosterone levels are normal but they’re progressing on an ARPi. And so in these blue states what we’ll be talking on for the next 20 minutes are these androgen pathway modulator-naïve or -sensitive disease states, which are patients responding to hormonal therapy.

So another key point is that doublet therapy, at least, at a minimum, is really improving survival, and this is just 1 slide showing you an example from our paper, also about a month ago in European Urology, showing that enzalutamide improves 5-year survival and that risk groups can be constructed where now the 5-year survival of all comers is around two thirds of patients. That’s a 13% improvement over ADT alone. And you can see phenomenal survivals based on whether a patient’s low volume or high volume. You’ve seen this data now with abiraterone/apalutamide from the ENZAMET trial from the LATITUDE and STAMPEDE cohorts with darolutamide. This is basically to say that ADT monotherapy is no longer standard of care and that we should be pursuing treatment intensification for the vast majority of patients.

When a patient starts with therapy we often see things get better. PSAs go down. PSAs can reach a nadir typically after starting hormonal therapy with ADT and an ARPi within about 6-12 months, and in this paper we also showed that an undetectable PSA at that 6-12-month landmark is associated with nearly an 80% chance of 5-year survival. In the lower right this is the ECOG CHAARTED data with docetaxel, no ARPi, also showing an undetectable PSA achieving similar important landmarks now at 10 years. Others have shown circulating tumor cells and cell-free DNA metrics as being important decisions that can identify different prognostic groups of patients.

So moving on to some new data also from this year, many doctors will use a GnRH agonist or antagonist, but we haven’t to date had a lot of data with the new oral GnRH antagonist relugolix in combination with some of our more commonly used androgen receptor pathway inhibitors. So this study took a look at drug/drug interactions, pharmacokinetics, pharmacodynamics, safety and efficacy of 2 different cocktails, abiraterone/relugolix, apalutamide/relugolix. They quickly realized that using apalutamide with relugolix led to a suboptimal level of hormonal suppression. Only 83% of men achieved a testosterone under 20. With abiraterone this did not have those same drug interactions. This is due to a cytochrome P45 3A4 induction by apa, which lowers the concentrations of relugolix. So in this article they recommended that the dose of relugolix be doubled to 240 mg, just something that many practitioners may not have encountered in their everyday reading, so if you’re choosing to use apalutamide with relugolix you need to double the dose.

Dr McKay has looked at relugolix in short-term therapy. As we know, hormonal therapy can improve the cure rates of men with localized disease, particularly unfavorable, intermediate- and high-risk disease. And the point of this study that was presented 2 weeks ago in San Francisco, Abstract 122, was that real-world use of relugolix was very well tolerated, that most patients are able to complete a 6-month course with only rarely having to discontinue, and compliance was excellent. Cardiovascular AEs were very rare during this period.

To me, this doesn’t really answer the question of should you be using relugolix versus a GnRH agonist or an injectable. The advantage, obviously, of relugolix is its rapid on, rapid off, so if you’ve got a guy who’s only going to be on therapy for 4 to 6 months that rapid off period of rapid testosterone recovery is obviously a big advantage for relugolix. We don’t yet know whether the cardiovascular safety differs between an antagonist and an agonist, with retrospective studies suggesting perhaps better cardiovascular safety for the antagonist but prospective studies not showing that.

Another trial in progress looking at hormonal therapy is advertising an ultra-hypofractionated radiotherapy scheme, really just 5 fractions, which is phenomenally quick, along with relugolix. This is a trial in progress called ULTRA-HERO, where patients who are undergoing this form of therapy will be followed for their primary endpoint of an undetectable PSA.

I’d like to highlight the EMBARK study. Over the past 2 years this is really a practice-changing landmark study. The EMBARK study took patients who had PSA relapse after local prostatectomy or radiation, had a rapid PSA doubling time, less than 9 months, no metastatic disease on CT, bone scan or MRI, and were randomized to enza/ADT, ADT with placebo or enza monotherapy, with a primary endpoint of metastasis-free survival. This is really a long-term surrogate endpoint of overall survival. And because this was a positive study this led to the FDA approval of both enza monotherapy, as well as the combination.

If you take a step back and say well, did these patients have metastatic disease. On PSMA imaging an EMBARK-like population of 182 patients with very similar or identical enrollment characteristics almost all had metastatic disease on PSMA PET imaging. 84% were actually M1, suggesting that the EMBARK-type patient does have metastatic disease, just micrometastatic disease not yet visible on conventional imaging.

And the PSA Working Group recently published some guidance around the terminology for this population. Prostate Cancer Working Group 4 and the PSA Working Group use slightly different terminologies. Either way, I think it’s important that we specify the type of imaging that we’re using to define metastatic disease because patients with PET-only disease actually have a much better prognosis.

The outcomes of these high-risk BCR patients were improved with the combination over ADT alone. You can see on the left here impressive improvement in the 5-year survival rate, a metastasis-free survival from 71 to 87%. This hazard ratio’s 0.42. I just put up on our right-hand side our ARCHES data, which is conventional metastatic patients treated with the same regimen. Hazard ratio’s 0.39, nearly identical. So whether you’re treating micromets or macromets you see a relative improvement in progression-free — radiographic progression-free survival and overall survival in this patient population.

This was mirrored by improvements in overall survival as well. Again, hazard ratio’s around 0.6, very similar between ARCHES and the EMBARK study.

Now, the enza monotherapy did not improve survival but was essentially equivalent to ADT alone, suggesting that this may be an acceptable alternative for patients who are unable to tolerate or wish to not receive androgen deprivation therapy.

Now who benefits from this form of treatment intensification? Really all subgroups benefited regardless of the PSA doubling time, age, geographic region. This forest plot right in the middle, all of these lines are to the left of 1.

The most common treatment-emergent AEs, importantly, to realize are hot flashes, fatigue and hypertension, with gynecomastia being a fairly unique adverse event with enza monotherapy due to the reflex increase in serum testosterone.

Now, a big issue is treatment duration and suspension. So after about 36 weeks if patients achieved an undetectable PSA they got to take a treatment holiday. How long did that holiday last? Well, about a year and a half to 2 years for the combination, only about a year and a half for ADT alone, and less than 1 year for enza monotherapy.

And that’s because enza wears off quickly, the patient already has high testosterone, and you see a relatively rapid rise in PSA once you stop that agent. So when I’m counseling patients the enza combination with ADT is something that provides improvements in survival and actually a longer treatment break, so that’s my default regimen.

Now, there are some patients that may benefit from enza monotherapy. This data supports some improvements in sexual health particularly during that treatment-free interval. With enza monotherapy there’s a more rapid recovery since you’re not going through ADT alone. That is not seen with the combination. But like I said, this recovery period is shorter when you stop enzalutamide monotherapy, so this recovery of sexual quality of life may be short but still worth it to some patients.

Now, there’s some ongoing trials trying to build on enzalutamide in this setting. ARASTEP is 1 such example, where again patients with no conventional metastases are randomized to darolutamide or placebo. These patients are required to have PSMA PET evidence of metastatic disease and a rapid doubling time, less than 12 months. MDT, or metastasis-directed radiotherapy, is permitted on this study.

And the primary endpoint here is a little controversial. It’s radiographic progression-free survival by PSMA PET imaging, which as I just mentioned on our first slide, Prostate Cancer Working Group 4 has only recently defined, 2 weeks ago, but is not a validated and acceptable endpoint to the FDA. Fortunately, ARASTEP is also measuring conventional imaging, so this may be one of the first studies to qualify PSMA PET progression-free survival as a potentially approvable endpoint.

Now, moving hormonal therapy into even earlier settings. We’re all aware of the STAMPEDE data for abiraterone actually improving survival in very high-risk patients with localized prostate cancer in conjunction with ADT and radiation. The ATLAS trial is doing that same kind of approach with apalutamide versus placebo and bicalutamide, all treated for 2 years and with radiation, with a primary endpoint being metastasis-free survival. This has not been read out yet.

However, the ENZARAD study, which is very similar, more high-risk than very high-risk disease, did read out recently at ESMO and did not meet its primary endpoint. However, there were some suggestions that enzalutamide improved outcomes in patients with pelvic lymph node metastases, so that’s a subset analysis of this prospective Phase III study.

The final localized but high-risk patient population study is the DASL HiCaP study looking at both high-risk up front and high-risk biochemical recurrence, patients randomizing to darolutamide or placebo, another important trial in progress to be aware of.

Finally, the earliest possible use of these forms of treatment intensification is neoadjuvant to surgery. The PROTEUS study will likely read out in the coming year. This is a pre-prostatectomy treatment where patients are randomized to ADT plus or minus apalutamide. They will all undergo prostatectomy, pelvic lymph node dissection and then be treated with a period of adjuvant therapy post-prostatectomy with or without salvage radiation.

The primary endpoint of this is metastasis-free survival, but an important endpoint will be pathologic CR. Much like in breast cancer how pathologic CR is often useful for early approval and signal finding this will be the first study to really evaluate path CR as a surrogate marker for metastasis-free survival later. Again, we don’t have results of this study yet.

Finally, just like EMBARK, apalutamide has also been evaluated in this high-risk BCR population. The PRESTO study, presented by Rahul Aggarwal from UCSF on behalf of the NCI Cooperative Group Alliance, looked at really triplet hormonal therapy, apa/abi doublet, apa/ADT versus ADT alone with a PSA-based endpoint.

This trial did meet its endpoint for delaying PSA progression-free survival, hazard ratio 0.72, but in the final analysis published just recently by ESMO as an abstract the hazard ratio for a more hard endpoint, metastasis-free survival, was not met. This could be simply because the study was underpowered, it was much smaller with more limited follow up than the EMBARK study, but as of now enzalutamide is the only agent that has what we would call Level 1 evidence in this high-risk BCR population and it’s the only one that has FDA approval in this setting.

Finally, ARANOTE in the metastatic hormone-sensitive setting did improve responses, improved radiographic progression-free survival, is immature for overall survival but still led to the FDA approval in the past year as an alternative doublet and is now in NCCN Guidelines because of this progression-free survival improvement.

Darolutamide is one of the optimal ARPis because it doesn’t penetrate the blood-brain barrier. It’s associated with great PSA declines, improvements in survival in several disease states, does not have as many adverse events, such as fatigue, falls or fractures or high blood pressure, and has a favorable effect here in ARANOTE on delaying quality-of-life deterioration. And you can see from Dr Morgans’s presentation at ASCO is that a favorable PSA decline to undetectable is associated with greater maintenance of quality-of-life changes. And this is seen here on the FACT-P score as well.

A common question is do I really need docetaxel. So a triplet therapy involves ADT, and ARPi and docetaxel. We have Level 1 evidence from the PEACE study and the ARASENS study with darolutamide or abiraterone that docetaxel for 6 cycles can improve survival. But there are many older patients that don’t tolerate docetaxel very well, even for the 6 cycles.

And this is a very innovative study called the ARASAFE study where all patients were given a triplet, but they were randomized to the conventional treatment of docetaxel every 3 weeks at 75 mg/m2 or 50 mg/m2 every 2 weeks, which has been studied in more advanced settings as more tolerable.

And in this ARASAFE study the every-2-week regimen met its primary endpoint of significantly reducing Grade 3/4 adverse events from 78 to 61%, neutropenic fever or death was reduced from 64 to 24%, and the risk of neutropenic fever also reduced from 5.5 to 1.7%. This was maintained at a similar efficacy, so this suggests to me that patients who are more vulnerable, frail or at high risk of neutropenic fever could consider this alternative every-2-week regimen.

Finally, CAPItello in the hormone-sensitive setting. This is probably one of the more impactful presentations and publications. These are patients with PTEN-null prostate cancer all in the hormone-sensitive setting. We know that PTEN deficiency is associated with a worse prognosis in this disease. In the CAPItello-281 study patients received placebo plus abiraterone/ADT, that’s the doublet, or this new triplet of capivasertib, which is an AKT inhibitor.

Primary endpoint was rPFS, and the primary endpoint was met. It delayed rPFS, so the first trial to delay progression-free survival in this hormone-sensitive setting by a large amount, by almost 8 months, meeting its primary endpoint with a significant p-value.

Now, overall survival is still immature; only 26% maturity. There is a favorable trend at this time for overall survival but not yet significant.

And so as we’re trying to make decisions, will the FDA approve this, we’re also looking at quality of life, how patients feel and function during this time. We do see that the use of capivasertib leads to a pretty trivial but important drop in quality of life, followed by resolution as doctors will dose reduce capivasertib for certain toxicities, and we see generally a maintenance of high quality of life due to this.

Now, we do see some discontinuations of capi due to adverse events. That’s largely going to be diarrhea, hyperglycemia and rash. And whether those added Grade 3 adverse events are worth the delay in progression-free survival without a survival benefit I think remains to be seen.

And my takeaways is it’s unclear if this really represents a new standard of care without that improvement in survival. This is a major unmet need population. PTEN loss is clearly associated with worse progression-free and overall survival. This is some data that we have that is in a manuscript that we submitted showing PTEN loss associated with worse progression-free and overall survival in a large national registry. So I hope that the CAPItello study results in improved survival, but as of now we don’t have such data.

Finally, PARP inhibition has recently made it to NCCN Guidelines and FDA approval in the hormone-sensitive study, and that’s based on the AMPLITUDE study. These are patients with hormone-sensitive disease treated with abi plus or minus niraparib, a PARP1/2 inhibitor. The FDA recently approved this selectively for BRCA2-mutated patients, and that’s because of a hazard ratio that was nearly 0.5 and highly significant. There was no clear benefit in the non-BRCA homologous repair-deficient patients, and so that group was not included on the FDA approval list.

We have ongoing Phase III studies of different PARP inhibitors, such as talazoparib in TALAPRO-3, such as saruparib, a selective PARP1 inhibitor in EvoPAR-01.

And so right now the final slide here in the NCCN Guidelines and hormone-sensitive algorithm does list niraparib and abi for patients with BRCA2 mutations as one of the many suite of options to offer. Certainly docetaxel as a triplet does improve survival, so we’ll be faced with trying to decide should you give niraparib or docetaxel to a high-risk or high-volume patient.

I can finish with a few clinical trials in progress. Certainly, these are in more advanced settings, what we call hormone-resistant settings, so patients who have already had an ARPi, they’ve progressed. But there are some newer hormonal therapies coming. Merck has a drug called opevesostat, a CYP11 inhibitor. This is a very high upstream androgen synthesis enzyme, so when you block that you block adrenal androgens, glucocorticoid androgens. All mineralocorticoids and glucocorticoids and adrenal androgens are suppressed, so you have to give this agent with dexamethasone and fludrocortisone to support the patient during that risk period for adrenal crisis. So ope with dex and fludrocortisone is being compared to a second ARPi in this trial in progress, OMAHA trial, both prior to and after chemotherapy.

So the TulmiSTAR is a trial in progress poster we presented just a few weeks ago at the GU symposium. This trial is taking 2 novel agents, so tulmimetostat is an EZH2 inhibitor, EZH2 is really important for directing lineage plasticity in ARPi resistance, and luxdegalutamide is a novel AR degrader. So the rationale between the 2 drugs is that prostate cancer can emerge and develop hormone resistance through 2 pathways; one is through AR, where AR’s amplified and the activity is maintained, and the second is a bypass around AR, where EZH2 is important. And here we’re blocking both pathways to see if we can bottleneck the tumor evolutionarily and thus delay/prevent resistance, and we hope that that will translate to better survival.

So this is a Phase I/randomized Phase II where the optimal dose of both drugs will be combined together and then tested against the best physician’s patient standard of care option. So we hope that this will lead to a larger controlled study in the near future, once that dose optimization has been completed.

Other Available and Emerging Therapeutic Approaches — Scott T Tagawa, MD, MS

DR TAGAWA: Hi, my name is Scott Tagawa. I'm a medical oncologist at Weill Cornell Medicine New York-Presbyterian Hospital Meyer Cancer Center. I'm very pleased to join Neil Love to discuss year in review, at least partially, of what my partner, Andy Armstrong, will do the rest in terms of what has happened in 2025, which has really been exciting for both me as a physician treating prostate cancer and other GU malignancies, as well as a researcher, and even more importantly for our patients.

So to go through just to highlight things I'm going to show several different studies that have utilized the combination of a PARP inhibitor and an AR pathway inhibitor. And by way of background, scientifically, there's some preclinical data that there is an interaction between AR and PARP within the nucleus.

And then the background for this particular study called PROpel. There was a randomized Phase II led by Noel Clarke that had interesting data that the combination of abiraterone/prednisone plus olaparib was better than abiraterone/prednisone. It had a potential safety signal in terms of cardiovascular, but that led to this trial called PROpel, which looked at the combination of abiraterone/prednisone with olaparib versus abiraterone/prednisone in an all-comer patient population. That was everyone who was enrolled, regardless of germline or somatic alterations, with the plan to analyze an HRD population as well as the all-comer population.

And that part was, hopefully most of the audience is aware of this, so that was initially published for the primary endpoint of rPFS, led to approval of this particular combination. And what we've seen more recently is additional follow-up. So the Phase III, as I said, was positive for rPFS, particularly in the HRD patient population, which was the subset, which was really driven, not surprisingly by the BRCA patient population.

And then we have longer-term follow-up in terms of overall survival that, not fully powered for overall survival, but not officially hitting overall survival, although each individual subset, as we go to all comer, to HRD, to BRCA, is closer and closer to an overall survival signal. So we don't really know for sure that there's an overall survival advantage of doing the combination versus maybe sequential single agents. I'm going to get to an intriguing study with that. But additional follow-up has shown that this combination does make sense.

A caveat to this study, and all the studies I'm going to talk about, is that the patient population that went in was, in general, naïve to an ARPI. And since we're using it much earlier, a wave of studies that was done in an earlier patient population is maybe a little less clinically relevant.

So another study, same kind of concept, ARPI plus a PARP inhibitor, different PARP inhibitor, talazoparib, again, in an unselected patient population with a plan to enroll everyone, treat everyone, and look at the HRD patient population. Very similar result. This is just the use of a different ARPI. And I do think it's important because sometimes in individual patients it might be better for enzalutamide versus abiraterone. So this allows us to have options when we want to use that combination.

If we think one of the ARPIs is going to be better for that individual patient based upon comorbidities or drug-related interactions, things like that. So again, this study was initially presented and published for the rPFS benefit, led to approval for the combination, again, in patients that have HRD and have not been exposed to PARP inhibitor, I'm sorry, ARPI is not exactly on the label, but that's per the guidelines. Very importantly, and I would say impressively, in the follow-up, which was presented and published, is that there is actually an overall survival signal. So a bigger study. And then that was subsequently enriched in an additional cohort for patients with HRD.

But overall, it was positive for overall survival, and a very impressive hazard ratio for overall survival, which was about a 50% reduction in death for this combination. So, again, I think that for a patient that has not been exposed to an ARPI in the situation that has, I'm sorry, I didn't mention the abbreviations, metastatic androgen pathway modulator resistant disease, so this is our new terminology, instead of castration resistant.

It, number 1, encompasses all of the different hormonal therapies that we have now and in the future, and gets away from, and uses more patient-friendly language. So we all need to get used to it. So formerly CRPC, now APMR disease. But when they're naïve to ARPI, then the combination makes sense. And this particular one has a survival advantage. And this is just another slide to emphasize that with the — this is the actual follow-up data.

MAGNITUDE was a similar type of a study that enrolled a broad patient population. However, it was separated into an HRD group and a non-HRD group. And the non-HRD group was clearly negative. The HRD group was positive for the rPFS. And like the other studies was, this had a little bit of extra prior ARPI, but a very small percentage, positive for the primary endpoint of rPFS, leading to the label for this particular combination. And in additional follow-up, what we see is no overall survival difference. Better, not surprisingly, in the subgroup with BRCA1 or 2 but not overall survival advantage for this.

Taking a step back, what I didn't show, it was on one of the slides, but I didn't really show the adverse events. I think it's important to know that there are adverse events from both drugs. It makes sense, right? This is a combination. There's going to be adverse events with PARP inhibitor, adverse events with ARPI. They're not all overlapping, but, for instance, anemia can happen with hormonal therapy, can happen with a PARP inhibitor. Many of these studies were done with restrictions on what could happen as it was going from Grade 2 to Grade 3 and couldn't intervene until it was Grade 3.

So in the real world hopefully we can intervene and identify and dose reduce or hold or give a growth factor transfusion. But it is important to know that there are some overlapping toxicities that might happen with the combination.

Okay, so shifting. Another study that is a combination of a similar patient population. So metastatic APMR disease, formerly mCRPC, that was mostly naïve to ARPIs, was randomized to ARPI alone or ARPI with radium-223, primary endpoint of rPFS. That was presented at ESMO and subsequently published. What we're seeing more recently is the actual data presented at ASCO GU just recently, was the overall survival. So there was an overall survival signal based upon the initial presentation and publication, but as you see on the right, because of the crossing of the Kaplan-Meier curves, officially,

They couldn't say for sure it was statistically significant. Now with additional follow-up, there is a statistically significant overall survival advantage for this. So again, we don't always see patients that have APMR-resistant disease that are naïve to ARPIs.

But when we do see that, and I would say when they have bone mets, which is most of the time, when enzalutamide is a good treatment option, not everyone can handle that or drug-drug interactions, but I think it's a good choice. There were no restrictions on soft tissue disease other than visceral. So it makes sense because they have, there is a big lymph node. Well, enzalutamide should be able to handle that. And then radium can also contribute to that bone compartment.

Importantly, what happened, and some of you might be familiar with what's called the ERA or ERA223 study, similar study done slightly earlier with first-line abiraterone with or without radium, that was a negative study and was stopped early for safety because of fractures. And those were both pathologic as well as insufficiency fractures. This study had the benefit of seeing those data and having an early amendment that mandated a bone health agent. So this overall did not have excess fractures because of early amendment.

So I think probably all patients getting radium, unless there's a contraindication, should get a bone health agent, especially using this combination. Otherwise, there could be excess fractures. So now becoming part of the guidelines when we see this patient population.

Okay, this is what I alluded to. So this is an investigator-initiated study that was done through The Prostate Cancer Clinical Trials Consortium, actually at an earlier era. So there wasn't so much earlier RP use at that time. We had no real combination data. And unlike the other studies, this was, you can see in the schema, a 4-arm trial, but really focus on the left, that 1 to 1 to 1 randomization, a 3-arm trial, looking at, in a BRCA1/2 or ATM mutated patient population, abiraterone/olaparib, or the combination with the allowance for crossover.

And Maha Hussain presented this initially positive for the primary endpoint of rPFS. What we saw at ASCO GU 2026 is more mature data that includes crossover data, includes overall survival data, and show the data for the other exploratory cohort. I'm not going to mention that. But this is a small study, so we can't make a lot of it, but it's the only one that's really looked at single agents, combination, including sequential single agents, which was about half of the, in each group that actually crossed over.

And what we can see, again with the caveat of small numbers, is that if we look at rPFS too, what happens after crossover with a combination as well as overall survival, it appears that the combination is superior. So really I would put this in the context of the randomized Phase IIIs that were just combination versus single agent not official crossover. And this one that included some crossover, I would say, in those patients that are naïve to PARP inhibitors that have germline or somatic repair defects, it makes sense to actually go in with the combination. Don't save the PARP inhibitor.

This provides evidence that the combination is probably the way to go for our patients. Of course, 2 drugs, maybe more side effects, but we need to manage that. And like we've done for many drugs, starting with historically with chemotherapy and other drugs, start very late, move earlier, same thing.

AMPLITUDE is the first randomized Phase III study to read out in the initial patient population. So APMN means naïve or APMS sensitive, formerly called hormone sensitive disease, to look at in an HRD patient population germline or somatic, what if we bring in the PARP inhibitor up-front at the backbone of abiraterone/prednisone because that's what has been shown to be safe with this drug.

There can be drug-drug interactions of niraparib with some of the ARIs. They were allowed to have some run-in with ADT and prior docetaxel. That was about 15% of the patients have about a month and a half of abiraterone if they wanted to. But basically this is asking the question of ADT/abi or ADT/abi and niraparib positive for the primary endpoint of rPFS. No difference in overall survival, but the point estimate in terms of the hazard ratio is favoring the combination.

And this actually led to the FDA approval, not of the overall patient population, but specifically the BRCA2 subset. And that's not shocking to me because when we look at the data, in all the trials, but in this trial, the stronger HRD agents or mutations tend to drive things. BRCA2, people say BRCA, but it's fairly clear that BRCA2 is a bigger driver than BRCA1 if I put all the data together. Fortunately, BRCA2 is the most common as well. So that's not surprising.

If you look at the FDA website, you can see the subset data that wasn't officially presented, but it now is in the public domain. So very impressive, if you ask me, data with a clear signal for rPFS and a strong trend for OS particularly in that BRCA2 patient population. So this is now primetime and FDA approved when you see these patients. They're out there but they're only there if you test. So we have to remember to test both germline as well as somatic.

Okay, so some of you I suspect have heard of PARP1 selective inhibitors. So everything we've been talking about so far are unselective PARP inhibitors. There was some data presented at AACR, I want to say 2 years ago with saruparib, which is a PARP1 selected inhibitor. It's a single agent with some interesting data across different tumor types that include some prostate cancer.

So what Arun Azad presented at ESMO 2025 was a combination trial using the PARP1 selective inhibitor saruparib with essentially all of the available ARPIs, at least in the Western world. And I don't want to make too much of it. There was, you can see at the bottom, there was some efficacy, PSA response. They were also getting the ARPI. So just remember that we can't — it's not a randomized trial to select out but it looked to be safe in terms of that. So, which I think I have on the next slide, that's led to additional trials. So there are, this is just one of the trials. And I think the next slide is better.

So there's EvoPAR-Prostate01 and EvoPAR-Prostate02. This was the 02 study. But EvoPAR-Prostate01 is basically the patient population that I showed in AMPLITUDE. So initial diagnosis of metastatic disease, ADT, this one is ARPI of choice because of the prior study that showed that safety with or without saruparib, looking at the primary endpoint of rPFS. This is EvoPAR02, which is going even earlier.

So essentially it's 2 parallel trials. If you look at Cohort A, which is called high risk, that is either primary radiation or salvage radiation. And you can see that that is ADT as kind of the standard with the radiation versus the addition of saruparib. Or in the de novo, very high risk that people often call STAMPEDE high risk, where ADT plus abiraterone, actually, we should put that out there because not everyone knows that when they're very high risk, high Gleason score, extraprostatic disease on the MRI, maybe a little bit of pelvic lymph nodes or very high PSA over 40, that gets us in the STAMPEDE high-risk group.

The standard of care is radiation with ADT and abiraterone for 2 years. This is adding to that backbone with saruparib. So we'll see what happens with this. I haven't mentioned so far, as we move this earlier, we also, of course, have to be mindful of the long-term toxicity. But hopefully, we'll see some efficacy.

And then another biomarker-selected type of a patient population, this is just a broader patient population. In a, moving back into the APMR-resistant patient population, I think almost everyone is aware of this study, where lutetium-PSMA-617 was superior for rPFS for that patient population post 1 ARPI, chemo naïve, led to the approval almost exactly a year ago, March 2025. The long term, or longer term, because it's not huge long term, but the mature OS data have been now published.

So officially no difference in overall survival, but hazard ratio of 0.91, at least looks to be no detriment in OS. The majority of patients, about three quarters, that had an rPFS event did cross over at around 7 months, that was the median to lutetium-PSMA-617. So it's testing earlier versus earlier.

And then what was, no major increase in adverse events with additional follow-up. So the top bar graph shows all-grade toxicity, when we look at those that got cycles 5 and 6 versus just 1 through 4, it doesn't appear to be more. This is self-selected. So someone that had more toxicity cycles 1 through 4 is not going to get 5 and 6. But it's nice to know with cycles 5 and 6 where there may be less PSMA tumor that's left, that there's no major safety signal. And then looking at amount of disease, as clinicians will know, that even in the ARPI group, you look at anemia, that's worse. And that's not so surprising to me. So longer term follow-up additional data that's out there.

And then moving it earlier to the AMPLITUDE patient population, but rather than selecting for HRD, that's PSMA PET. This study is not yet peer reviewed published, but we have 2 presentations on this. So ESMO 2025 and ASCO GU 2026. PSMA positive, a lower bar to have that. It's not the VISION criteria, it's just 1 lesion that's brighter than liver. Because the control is ADT ARPI. That should work. It's ADT ARPI of physician choice with or without lutetium-PSMA-617.

The primary endpoint is rPFS. This study was positive for rPFS with a hazard ratio of 0.72. Most of the secondary endpoints were either favoring the lutetium arm or not really different. On the high level that was presented at ESMO, no official difference in the patient reported outcomes, although maybe the number was a little bit with control. Mike Morris had the chance to go in that greater detail at ASCO GU.

And when we look at 1 of the instruments, FACT-P, during the initial 6 months, there was a trend for a little bit worsening of the overall quality of life with FACT-P, during the lutetium, but that caught up. It's not so different than, for instance, CHAARTED during chemotherapy. It was a little bit worse, but then later it was, there wasn't that detriment. The other 2 patient reported instruments, PRO instruments, EQ-5D and FACT, I'm sorry, BPI Short Form were no difference throughout. So overall, another potential option. This is not FDA approved. My understanding is it's been submitted, and we'll see what happens in terms of that and see what happens in terms of the guidelines.

And then, we've been looking to make immunotherapy work in prostate cancer for a very long time, we do have sipuleucel-T approved, but very clearly other than that very small MMR patient population, small but important to find, with the disease agnostic indications for PD-1 inhibitors, it just really hasn't worked. But bispecifics look very interesting. And this appears to be maybe the way that we're going to be able to have immunotherapy work. hK2 is analogous to PSA, it's not PSA, but it's analogous in that family that is specific to prostate cancer that is not secreted.

Pasritamig is a bispecific hK2 and CD3. And I think many of you are well aware of these bispecifics. This was a Phase I dose escalation study in a pretreated mAPMR patient population that did dose escalation of both subQ and IV dosing; subQ had a little bit more toxicity so we looked at the IV patient population. In my opinion, a very low adverse event rate. A very small percentage had CRS and when it happened it was Grade 1 and the regimen is an every 6-week regimen so extraordinary good tolerance when I think of the field of CD3 bispecifics with some, I think maybe on the next slide, with, that's more safety data, with some non-randomized, some signal of efficacy. So this drug has now moved into a randomized trial, either alone or in combination to try and get this into the clinic.

And then finishing with another targeted agent, but this will go to the realm of ADCs. And there are multiple different targets. We've talked about some, hK2, PSMA. This is B7-H3, which is a target of interest in multiple cancers, lung cancer, et cetera. But in prostate cancer, this appears to be especially in adenocarcinoma preserved, whether someone has initial disease or past APMR resistance.

And this particular, so I-DXd is a, I think many are familiar with the DXd platform of that linker with the topoisomerase inhibitor targeting B7-H3. So, had some initial data as a single agent. Two trials. So IDeate-Prostate01, which is a single agent, which is not shown right now, single agent looking for registration, head-to-head against docetaxel. So post RP, could have had prior PARP inhibitor, actually should have if they're eligible, could have had prior lutetium-PSMA-617, really going head-to-head against docetaxel, a targeted chemotherapy versus overall chemotherapy, the more potent warhead. Hopefully that's going to lead to approval.

What you see on this slide is IDeate-02, which is looking at combinations. So looking at different combinations with PARP inhibitors, or with the CYP11 inhibitor, opevesostat, which is separately in Phase III trials alone, but very interesting. So those who are not familiar with that, think of it as abiraterone except a step earlier, so more potent overall inhibitor of steroid biosynthesis. So I think that the future in many solid tumors, actually, even the present for many solid tumors, is ADCs rather than the kind of traditional cytotoxic chemotherapy, and hopefully we'll get there too in prostate cancer.

Thank you very much.