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Rashid Sayyid: Hello, everyone. And thank you for joining us today in this special NCCN recording of the 2024 key updates to the latest guidelines where we'll be discussing the M1 CRPC guidelines updates. I'm Rashid Sayyid, a urologic oncology fellow at the University of Toronto, and I'm delighted to be joined today by Zach Klaassen, associate professor and program director at WellStar MCG Health. There have been a lot of changes in these latest set of guidelines and here's a bit of an outline of the key points that we'll be touching upon.

First of all, we'll give our listeners a quick overview of the current agents that are FDA approved for the treatment of mCRPC patients. We'll talk about the current management algorithm of mCRPC patients. We'll have some key points that we often forget about. We'll talk about the treatment options for mCRPC patients, mainly those with adenocarcinoma based on the prior treatments received. We'll dive into the 2024 updates to these guidelines. And then we will discuss also, importantly, the evidence that informs these 2024 updates.

Here we've seen the schematic, all the agents that have been FDA approved for the treatment of mCRPC patients. Currently, we're sitting at around 16 approvals with the majority of these coming from 2010 onwards. Most recently, we've seen in 2023 really the emergence of the PARP inhibitor, ARPI combinations with niraparib and enza, olaparib and abi, and talazoparib and enzalutamide for patients with either BRCA 1/2 mutations or homologous recombination repair mutations.

Here we see in 2024 the current management algorithm for patients with M1 CRPC. And it's really important to note that progression to castrate-resistant disease doesn't just mean a PSA progression. It could be PSA, meaning biochemical, it could be clinical in terms of pain, for example, or radiographic. So it's really important to consider all these three aspects. And what's really important when we think about CRPC is, first of all, to confirm that patients are actually castrates. When we talk about castrate resistance, really we want testosterone levels less than 50. So it's very important in the clinic to make sure that patients, A, are actually receiving it, and then B, confirming that their testosterone is adequately suppressed. And what's important as well is to always stage these patients. The NCCN talks about imaging studies positive for metastases. So that means a CT chest, abdomen, pelvis, or in lieu of CT abdomen pelvis, you can consider an MRI with and without contrast as well.

Here are the different options that we have after we confirm a diagnosis of CRPC. Biopsying the metastatic lesion. So in addition to confirming that you have metastasis, the other door that it opens up is testing, somatic testing, for homologous recombination repair mutations or the microsatellite instability mismatch repair deficiency and tumor mutational burden, especially if these have not been previously done on the primary specimen. What this does is, it really opens up numerous treatment options for our patients that otherwise patients would not have been eligible for. And you don't have to biopsy every patient suspected of mCRPC, but doing so does open up this possibility.

Then the other thing we need to think about is that, in addition to the common adenocarcinoma, these patients, particularly the heavily pretreated patients that have advanced stage disease, can have small cell or neuroendocrine prostate cancer. And really there are some clinical signs as well as genetic changes that really should alert the treating physician that such a component may be present. When you see a patient with bulky disease, but at the same time low PSA or if they have a high carcinoembryonic antigen or an LDH level, these are some telltale signs that the patient may have either pure small cell neuroendocrine or may have a combination of adenocarcinoma as well as this neuroendocrine. And really that changes the treatment paradigm. So we'll talk about that some more, but it's very important to understand why the NCCN talks about potentially biopsying metastatic lesions.

What's important in all the patients, irrespective of the underlying pathology, is to continue the ADT in order to maintain the castrate levels of serum testosterone, again, defined as less than 50. But we'll see with the newer current testing kits that less than 20 really is the target and has been shown in many studies to be associated with better outcomes. It's very important for all these patients, in addition to focusing on the treatment of prostate cancer, to think about the supportive treatment options. So you have to always keep in the back of your mind the bone health. So bone anti-resorptive therapy, denosumab, which remains a category one or preferred regimen, or you can use zoledronic acid as well if bone metastases are present, which invariably they are in patients with mCRPC. Also, if patients are having painful bone metastasis, then consider palliated radiotherapy and always best supportive care as indicated.

So going back to the whole biopsy issue, if patients have not been biopsied, the NCCN tells us that it's okay to consider these patients as having a default adenocarcinoma and treating them based on that. And we'll discuss the different treatment options in the next few slides. But when we talk about the small cell neuroendocrine, you'll see here that the options are really quite different compared to what we're used to in classically adenocarcinoma. And I'm going to highlight one treatment modality that really has emerged probably as the best of all the current options, which is the combination of cabazitaxel carboplatin whereby in 2020 we saw a phase one-two trial of 160 mCRPC patients. And these patients were not only a small cell or neuroendocrine prostate cancer, but it could have been adeno or have a combination of both. In fact, we saw that over half of them had elements of both. So something very important to keep in mind.

And these patients were heavily pretreated. So about a third had docetaxel before and almost all of them had an ARPI before, a novel hormonal therapy, abi or enza. And these patients were randomized to receive either cabazitaxel alone or cabazi plus carboplatin and were followed for about two and a half years. And we see that this combination, so adding carboplatin to cabazitaxel, improved metastasis-free survival from four and a half to 7.3 months, which seems like a minimal change, but again, it really highlights the poor prognosis these patients have and the aggressive nature of this variant. So again, something to keep in mind when treating these patients.

Here we see a very busy slide that discusses the different systemic therapy options for patients with M1 CRPC, specifically the adenocarcinoma subtype. And the NCCN does a really nice job of breaking down the treatment options by the prior therapy received. We'll go over these individually, briefly highlighting the preferred regimens and the emerging ones as well.

If we start with patients who received no prior docetaxel or no prior ARPI, the "first-line" therapy options, the preferred regimens remain those that have been approved for a while now. So abiraterone, docetaxel, and enzalutamide, and we have the studies here that led to these approvals. But it's also important to keep in mind that recently we've seen, as I mentioned before, the combination of the ARPI and the PARP inhibitors for patients with BRCA or HRR mutation that really have emerged as category one recommendations useful in certain circumstances.

Next, when we discuss patients who've received the prior novel hormonal therapy such as abi or enza, but no docetaxel, really the consistent theme here is patients have seen a certain drug try to use a different drug with a different mechanism of action in order to not fall prey to the same mechanisms of resistance. So if they've received a prior novel hormonal therapy, try docetaxel. And different options that we've seen emerge and we'll discuss, and these are the changes or some of the changes that we've seen in these guidelines, is now that olaparib for patient BRCA mutation based on the profound trial and rucaparib as well for those with BRCA mutations with category one based on the 2023 TRITON3 trial have emerged as preferred regimens for treatment of these patients who've progressed before on a novel hormonal therapy. Again, this highlights the importance of early genetic testing in these patients in order to open up these very important and quite efficacious treatment options.

Next, if patients have progressed on prior docetaxel and have no prior novel hormonal therapy, so clearly abi and enza are options, but also we need to think about tropic, which was published in 2010 and really has shown the benefit of cabazitaxel in the post-docetaxel setting for these patients.

And now if patients have progressed on both a docetaxel and a novel hormonal therapy, we know based on the CARD data published in 2019, the cabazitaxel is a preferred regimen. And the docetaxel re-challenge is also reasonable. And this is particularly of relevance if patients have progressed on docetaxel in the hormone-sensitive setting. And this is something that's important as we see these agents being shifted further and further up the treatment paradigm. When we come to treat them later on, many of these patients are going to have seen many of these agents before, and it's really important to understand the value of these agents used in a re-challenge setting. Although this is not a preferred regimen but useful in certain circumstances, it's important to keep in mind that lutetium is a very attractive option specifically for patients with PSMA positive metastasis as a category one recommendation. And that's why it's considered useful in certain circumstances because we want to ensure that these patients are eligible based on the PSMA findings. And we know that there are different criteria, particularly in terms of incorporating FDT PET as we saw in the therapy trial.

Now, let's go over some of the changes that we've seen. Here we will highlight in boxes of different colors. What are some of the changes that we've seen to these NCCN recommendations? First of all, we see that pembrolizumab really has emerged as useful in certain circumstances for patients specifically with microsatellite instability high or DNA mismatch repair mutations for patients across really the treatment spectrum. So those have really seen no docetaxel or novel hormonal therapy before. Those have progressed on a prior dose but no NHT, and those who have progressed on an NHT with no doses. So essentially anybody who's either not progressed or progressed on one of the two agents. And we've seen that for patients that progressed on both even before, pembro has been indicated for a while. Really this option has emerged in all the different pre-treatment categories. So very important data we'll talk about as well, Zach will, about the evidence that really informs these changes in the guidelines.

Next, if we specifically focus on patients who've progressed on a prior novel hormonal therapy, as I mentioned before, now olaparib and rucaparib are both considered category one recommendations for patients with BRCA mutation. So very, very, very important for our patients. There are some minor changes in the useful in select circumstances that may or may not be of a lot of relevance, but it's important to highlight them nonetheless. So when we talk about a regimen that's modified, olaparib for HRR mutations other than BRCA 1/2 is no longer considered a category one recommendation. So a bit of a semantic change, but it's important to note, particularly when we think about the evidence that informs this. And then the regimen removed is rucaparib for BRCA mutation, and that's because now it's considered a preferred regimen and not just useful in select circumstances.

And then a very important change is that going from enza to abi or abi to enza is really no longer recommended by these guidelines. As I mentioned before, a common theme is when patients have progressed on a specific drug, we really want to challenge them with an agent with an alternate mechanism of action in order to overcome these resistance mechanisms. So although we know from Dr. Kimchi's group in the publication in 2019 that patients who go from abi to enza at about a 36% PSA response and conversely from enza to abi a bit worse, or actually significantly worse, about four to 8%, really the NCCN doesn't think that this really warrants a challenge with these drugs, particularly as we see so many different options emerge. So this is no longer recommended, going from abi to enza or enza to abi irrespective of the treatment received before. At this point, let's talk about the evidence that has informed these changes. Zach will go over the current evidence starting with pembrolizumab for patients with MSI high or DMMR mutations.

Zachary Klaassen: Rashid, thanks so much for that great overview and really highlighting these changes in the most recent NCCN guidelines. What we'll do over the next few slides is just go through some of the evidence that led to some of these key changes. So as Rashid mentioned, pembrolizumab really has emerged, and this story really starts in May of 2017 when the FDA approved pembro for patients with unresectable or metastatic MSI high or DMMR solid tumors who progressed on prior treatment and had no satisfactory alternative treatment options. And this is based on the results of five studies, 149 patients, and really agnostic approval. This was in colorectal non-colorectal patients. As you can see here, too, these patients in the studies were mCRPC, overall response rate was 40%. And among the mCRPC patients, one patient had a partial response and one had stable disease greater than nine months.

When we dig a little deeper looking at pembro specifically for mCRPC, one study looked at pembro plus enzalutamide evaluated in 10 mCRPC patients. These patients had non-visceral metastases and disease progression with prior enzalutamide. Of note, five of these 10 patients also received additional abiraterone, and there was near complete response PSA response in three out of these 10 patients. Two out of three had radiographic measurable disease and achieved a partial response, and one out of two patients with measurable disease had an MSI high tumor. Among these other seven patients, three had stable disease and four had no perceived clinical benefit.

Looking again at a few other studies. These are some early trials. KEYNOTE-028, phase 1B trial of pembro in 23 patients with advanced prostate cancer. 74% of these were heavily pretreated, more than two or more prior therapies for metastatic disease. The objective response rate was 17%. These were all partial responses. And stable disease was noted in 35% of patients. In the KEYNOTE-199 trial, this was a phase two trial of pembro and 258 mCRPC patients pretreated with either docetaxel or greater than or equal to one novel hormonal therapy. Unfortunately, the objective response rate for these was relatively low. Cohort one, which is PDL positive, 5%. Cohort two, which is PDL negative, was only 3%.

The NCCN statement for pembro is based on the available data. The panel supports the use of pembrolizumab in patients with MSI high or DMMR metastatic CRPC whose disease has progressed through docetaxel and a novel hormonal therapy. As we know from previous studies, the prevalence of MMR deficiency in metastatic CRPC is estimated at 2% to 5%. And testing for MSI high or DMMR can be performed using DNA testing or immunohistochemistry. Notably, if a tumor is MSI high or DMMR, the panel recommends referral for genetic counseling for consideration of germline testing for Lynch syndrome.

Now, when we look a little bit further at the pembrolizumab story, in June 2020, the FDA granted accelerated approval for pembro's use in patients with unresected or metastatic patients with a high tumor mutational burden. So this is another indication that was approved in 2020. This is among all solid tumors that have progressed following prior treatment and who have no satisfactory treatment options. The phase two KEYNOTE-158 trial included 790 patients. You can see the types of cancers here. Notably, no prostate cancer patients, but we do see an objective response rate of 29% in the tumor mutational burden high patients. The NCCN statement based on this KEYNOTE-158 trial is that, even though there were no patients with prostate cancer in this study, the panel concludes that pembrolizumab is an option for patients with mCRPC, prior docetaxel novel hormonal therapy, and a tumor mutational burden greater than 10 mutations per megabase based on extrapolation from other tumor types. So these are several of the important updates. Of course, this is a small population among mCRPC patients, but notable in the NCCN updates for 2024.

So now let's switch gears to talk about olaparib and rucaparib as preferred regimens following prior novel hormonal therapy, but no prior docetaxel for BRCA mutations. And this really starts with olaparib in the PROfound trial. PROfound, as we know, is a phase three RCT of 380 CM CRPC patients with progression on enzalutamide or abiraterone. These patients were then randomized two to one to olaparib or the physician choice of enzalutamide or abiraterone. What's important here is there's two separate cohorts. Cohort A had at least one alteration in BRCA1, BRCA2, or ATM; and cohort B had alterations in any other of 12's pre-specified genes. As we can see on the Kaplan-Meier curves on the right, the primary endpoint was imaging-based progression-free survival among cohort A patients. This was a median progression-free survival of 7.4 versus 3.6 months favoring the olaparib-treated arm. Hazard ratio statistically significant at 0.34. And the secondary outcome at the time of the primary analysis was overall survival 18.5 versus 15.1 months favoring olaparib.

When we look at a subsequent publication that looked at the overall survival benefit in cohort A specifically, so this is just the patients with BRCA 1/2 or ATM mutations, on the left we see the overall survival in cohort A hazard ratio was 0.69, 19.1 months median survival for olaparib versus 14.7 months in the control arm. And when they did a crossover adjusted analysis, this is adjusting for patients that received subsequent therapies, this overall survival benefit increased to a hazard ratio of 0.42 favoring the olaparib arm compared to the control arm.

Why are BRCA 1/2 mutations only recommended for olaparib? And really the benefit here is not seen in ATM. And so we see that in this subgroup analysis of imaging-based progression-free survival, we see that the benefit for BRCA really is driven by BRCA2, hazard ratio of 0.21, very tight confidence interval. We also see a hazard ratio of 0.41 for BRCA1. The statistical significance is maybe subject here with the wide confidence interval. But really the take-home here is that ATM shows no benefit, hazard ratio of 1.04, confidence interval of 0.61 to 1.87.

Let's switch gears to talk about rucaparib. This is based on the TRITON3 trial, which was published in 2023. And this is looking at rucaparib after progression on an ARPI. Again, a phase three trial of 405 mCRPC patients with BRCA1/2 or ATM mutations, again, randomized two to one to rucaparib or the physician choice of docetaxel or the alternate ARPI. The Kaplan-Meier curves on the right show the primary and secondary outcomes. This is imaging-based progression-free survival. For the BRCA subgroup, this is at the top Kaplan-Meier curve, we see imaging-based PFS of 11.2 months versus 6.4 months favoring the rucaparib arm, hazard ratio of 0.50. And the intention to treat population, again favoring rucaparib as we see in this Kaplan-Meier curve, per imaging-based progression-free survival median of 10.2 months versus 6.4 months with a hazard ratio of 0.61. Again, we see no benefit in the ATM group, essentially overlapping Kaplan-Meier curve hazard ratio of 0.95.

When we look at the overall survival data, the maturity at the initial publication was quite low, still at 54% to 59%. In the BRCA subgroup at the top here we see 24.3 months versus 20.8 months, hazard ratio of 0.81 in the BRCA subgroup. And again, no surprise, zero benefit for overall survival in the ATM subgroup with a hazard ratio of 1.20 and nearly identical median overall survival.

To summarize this update of the NCCN, specifically for mCRPC patients, this update shows that pembrolizumab for MSI high DMMR tumors was added as useful in certain circumstances for patients with no prior docetaxel and no prior NHT. Those patients with progression on prior docetaxel and no prior novel hormonal therapy, as well as for progression on prior novel hormonal therapy and no prior docetaxel. And these were added as a category 2B recommendation.

When we look specifically at the progression on prior NHT and no prior docetaxel, preferred regimens were added for olaparib for BRCA mutation category one, as well as rucaparib for BRCA mutation, also a category one. As Rashid mentioned already, useful in certain circumstances, the regimen has been modified to no longer have olaparib for HRR mutations other than BRCA1/2, so it's no longer a category one recommendation. And the regimen was removed for rucaparib for BRCA mutation. Other recommended regimens removed: abiraterone, abiraterone plus dexamethasone as well as enzalutamide. So this is the ARPI switch, which is no longer recommended. And finally, progression on prior docetaxel and prior novel hormonal therapy, regimens removed, again, highlighting that the ARPI switch to abiraterone or enzalutamide is no longer recommended. We thank you very much for your attention and we hope you enjoyed this NCCN update of the mCRPC treatment guidelines.