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Rashid Sayyid: Hello, everyone, and thank you for joining us in this UroToday recording. I'm Rashid Sayyid, urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, associate professor and program director at Wellstar MCG Health, we'll be discussing the 2024 Key Updates to the NCCN Prostate Cancer Guidelines that were published on March 8th, 2024. In this recording, we'll be diving into the principles of non-hormonal systemic therapy, focusing on what's new in the guidelines and how we can apply this to our clinical practice.

When we talk about non-hormonal systemic therapy, we're really talking about various, quite different classes of drugs. We have chemotherapy drugs such as docetaxel, cabazitaxel, and mitoxantrone. We also have immunotherapy agents such as sipuleucel-T or Provenge and pembrolizumab. But significantly in this update, we really see the emergence of PARP inhibitors, with a plethora of data looking at biomarker-driven research in this field.

In the PARP inhibitor space, we have olaparib monotherapy and rucaparib monotherapy. We also see combination therapy with olaparib plus Abi, niraparib plus Abi, and talazoparib plus enzalutamide. This research and these recommendation updates have also been reflected in regulatory approvals whereby, if we look here at the timeline of the FDA approvals in the mCRPC disease space, and highlighted in red are the changes that we're focusing on, we see that in 2020, we had olaparib and rucaparib approved for patients with homologous recombination repair mutations, HRR, as well as BRCA mutations for rucaparib. And then more recently in 2023, we've seen three different combinations approved for a variety of patients with specific mutations.

This is an overview slide that highlights the changes that have been made in the NCCN guidelines, particularly pertaining to the PARP inhibitor monotherapy drugs. We'll go into this in further detail later, but I just want to highlight what the changes are. If we look at the top right panel here in patients who have progressed on prior novel hormonal therapies or ARPIs such as Abi, Enza and had not received prior docetaxel, currently, olaparib among patients with BRCA mutations and rucaparib as well, similarly, for those BRCA mutations, are now considered preferred regimens, whereas previously they were considered useful in certain circumstances. So definitely a stronger endorsement now by the NCCN for the single-agent PARP inhibitor use in this setting. We also see that now olaparib is considered useful in certain circumstances for patients with HRR mutations other than BRCA1 and 2.

Let's dive into this further. Let's start with olaparib monotherapy. In 2020, we had the PROfound trial that looked at olaparib in patients who had progressed on prior enzalutamide or abiraterone. This was a phase III RCT of about 400 patients of mCRPC who had progressed on these drugs and were randomized 2:1 to either olaparib or the physician's choice of the alternate ARPI, Enza or Abi. In cohort A, this was where the study was powered, these patients had at least one alteration of either BRCA1, 2, or ATM. In cohort B, patients had alterations of any of the 12 other pre-specified genes as long as they weren't any of those three.

This trial met its primary endpoint whereby progression-free survival was improved significantly in cohort A, almost doubled from 3.6 to 7.4 months. Overall survival, as we see in the Kaplan-Meier curve here, was also improved by just over 3 months. Later on, what the authors did was they adjusted, essentially, for patients crossing over from the control to the interventional. So although we saw about a 3 to 4-month benefit for olaparib, when we considered the fact that 67% of patients in the ARPI switch subsequently crossed over to receive olaparib, we noticed that this benefit is even more pronounced, with the hazard ratio of 0.42, whereas it was 0.69 before. Again, this reaffirms the importance not only of giving olaparib but early olaparib monotherapy in these patients.

And so, why is the focus on BRCA1 and 2 only and not also ATM? ATM patients were a part of cohort A, but when we look at the subgroup analysis looking at the outcome of imaging-based progression-free survival, we see that the benefit is almost exclusive to those with BRCA1/2 mutations, with the hazard ratios of 0.2 to 0.4, whereas when we look at the ATM subgroup, the hazard ratio is essentially null at 1.04. So quite clearly the benefit that we see in cohort A is almost exclusively, if not completely, related to the BRCA1/2 benefit only.

Based on the current evidence, what are the NCCN recommendations for olaparib monotherapy? We touched on this earlier, but we'll also confirm this again, whereby in patients who have progressed on prior novel hormonal therapy but have not received prior docetaxel, olaparib is a preferred drug for patients with BRCA mutations, can be useful in select circumstances for patients with other HRR mutations, and even in patients who have progressed on prior docetaxel and a novel hormonal therapy, olaparib can be useful in certain circumstances for patients with HRR mutations.

Next, let's move on to rucaparib monotherapy. Here we see TRITON2 was published in 2020 and evaluated rucaparib in mCRPC patients who had progressed on both ARPIs and taxane chemotherapy before. This was a phase II single-arm trial of this drug given orally twice daily in about 300 mCRPC patients who had DNA damage response mutations who had progressed on these drugs. And although all of them had DNA damage response mutations, the BRCA1/2 mutations were only present in about two-thirds, but also, mutations of note were ATM in 21%, CDK4 in 5%, CHEK2 in 3%.

Now, focusing on the BRCA patients, the objective response rate was almost 50% with a complete response of 10%, and we see that the response was better in those with BRCA2 as opposed to BRCA1 mutation. There are some hypotheses that the BRCA1-mutated patients had other mutations such as TP53, etc., that really nullify or kind of dilute the effect of these drugs in these agents.

When we look at the PSA50 response in the BRCA-mutated patients, this was about, again, 53%, and the median overall survival for these BRCA patients was about a year and a half and significantly better than other mutations, which were roughly at around a year, which, again, highlights the benefit of these drugs in the BRCA-mutated patients.

Next, in 2023, we saw TRITON3 published in the New England Journal of Medicine, and this is the trial that's analogous to PROfound for rucaparib. And so these are patients who have progressed on a prior ARPI with a phase III trial of about 400 patients. These patients were randomized two to one to rucaparib or physician's choice control, which could be docetaxel or an alternate ARPI, whereas in PROfound we saw an alternate ARPI only. Here, this included patients with BRCA1/2 or ATM mutations only.

This trial met its primary endpoint with an improvement in the imaging-based progression-free survival in the BRCA subgroup at 11.2 versus 6.4 months, so almost double. The intention-to-treat population was 10.2 versus 6.4. So again, a larger magnitude of benefit in the BRCA-mutated patients. And again, no benefit in the ATM group, as we see here in the Kaplan-Meier curve, where essentially the curves mirror each other in the ATM subgroup.

Now, looking at overall survival, the data maturity is only about 54-59%. We see that in the BRCA subgroup we have about a 3 to 4-month benefit. ATM subgroup, again, no overall survival benefit.

So based on the current evidence, what are the NCCN recommendations for rucaparib monotherapy? Similar to olaparib, in patients who have progressed on prior novel hormonal therapy and no prior docetaxel, rucaparib for BRCA mutation is a preferred regimen, whereas now in patients who have progressed on prior docetaxel and a novel hormonal therapy, so this is essentially the TRITON2 cohort, rucaparib is useful in certain circumstances for patients with BRCA mutations. At this point, I'll turn it over to Zach who'll go over the evidence and the changes in the guidelines for PARP inhibitor combinations in the mCRPC setting.

Zach Klaassen: Rashid, thanks so much for that great introduction and for the review of the monotherapy. We're going to focus on PARP inhibitor combinations for the rest of the presentation, which is specific to the NCCN guidelines. We've seen a version of this figure already. The red box is essentially to highlight some of the key changes and the most up-to-date recommendations from the NCCN.

The first point here that should be made is in the no prior docetaxel, no prior novel hormonal therapy patients, there's category 1 for all three combinations, and this includes niraparib plus abiraterone in BRCA-mutation patients, olaparib plus abiraterone in BRCA-mutation patients, and talazoparib plus enzalutamide for HRR mutations. When we move to the right of the screen, this is progression on prior novel hormonal therapy, but no prior dose of taxane. We see two category B recommendations for niraparib plus abiraterone for BRCA-mutation patients and category B for talazoparib plus enzalutamide in HRR mutation patients. Finally, at the bottom, when we look at patients with progression on prior docetaxel but no prior hormonal therapy, we see recommendations for niraparib plus abiraterone and olaparib plus abiraterone for those with BRCA mutations and we see a recommendation for talazoparib plus enzalutamide for HRR mutation patients.

Let's look further at olaparib plus abiraterone in this setting. First, let's look at the PROpel trial. This came out in 2022. This is the trial design. These were first-line mCRPC patients. Docetaxel was allowed at the mHSPC stage, but no prior abiraterone was allowed, and these were all high-performance patients, ECOG 0 to 1. These patients were then randomized 1:1 to olaparib plus abiraterone versus placebo plus abiraterone, with a primary endpoint of radiographic progression or death, and a key secondary endpoint of overall survival.

These patients had a median PSA of 17 to 18. 25% of these patients received prior docetaxel. The most frequent set of metastases was in the bone at 85-88%, and HRR mutations were present in 29% of patients, specifically BRCA1/2 patients, 10.7%. You can see on the Kaplan-Meier curve on the right, the primary outcome was investigator-assessed radiographic progression-free survival, which significantly benefited the intervention arm at 24.8 versus 16.6 months, with a hazard ratio of 0.66 favoring abiraterone plus olaparib, which was statistically significant. When we look at the HRR mutation patients, the hazard ratio was 0.5, and for non-HRR mutation patients, the hazard ratio was 0.76.

In updated OS data, we see that there's a maturity of about 50% at this point in the analysis. The ITT population for Abi plus olaparib, 42.1 months versus 34.7 in the Abi plus placebo group, hazard ratio of 0.81, p-value 0.054. In the HRR mutation patients, the hazard ratio was 0.66. In the BRCA-mutation patients, we see significance at a hazard ratio of 0.29 and a 95% confidence interval of 0.14 to 0.56, and at this point, no signal in the non-HRR mutation patients.

Now we'll switch to the niraparib plus abiraterone patients. This is the combination therapy from the MAGNITUDE trial. Again, this is first-line mCRPC with less than or equal to 4 months of abiraterone allowed for mCRPC. Excellent performance status again. We can see prescreening for biomarker status, you could see the panel of mutations that were screened for, and then patients were divided into HRR biomarker-positive versus negative and then randomized at that point to niraparib plus abiraterone versus placebo plus abiraterone, with the primary endpoint of radiographic progression-free survival, and key secondary endpoint of overall survival.

In this MAGNITUDE analysis, the futility analysis was performed in the HRR biomarker-negative cohort. This essentially showed no signal with increased adverse events. So, this enrollment was suspended in the biomarker-negative cohort. In the biomarker-positive cohort, there were 423 patients. Patients had prior ARPIs for metastatic hormone-sensitive prostate cancer in 3% of the population and prior taxane therapy in the same disease space in 20% of the population.

The primary outcome, which you can see on the right for HRR-positive mutations in panel B, was 16.5 versus 13.7 months, favoring the combination therapy, hazard ratio of 0.73. In the BRCA1/2 population, we see an improved outcome, again, a little higher magnitude at 16.6 months versus 10.9 months, with a hazard ratio of 0.53, 95% confidence interval of 0.36 to 0.79.
Looking at an updated analysis that was published in 2023, this is after 24.8 months, we continue to see an improved signal in the BRCA1/2-mutation patients, 19.5 months versus 10.9 months. Solid hazard ratio of 0.55, statistically significant confidence intervals. We do not see an OS benefit with 73% data maturity, with a hazard ratio of 0.88.

Moving on to the final combination, this is talazoparib plus enzalutamide, and this is the TALAPRO-2 trial, which came out in 2023. Again, very similar to the previous two trials. First-line metastatic CRPC. Excellent performance status. We do see, in cohort one, this included the non-deficient or unknown patients at 636, as well as the HRR-mutation patients, 169. Cohort two was a combination of the HRR-mutation patients only, and this was 399 patients. These patients were then randomized 1:1 to talazoparib plus enzalutamide versus placebo plus enzalutamide with, again, a primary endpoint of radiographic progression-free survival, and a key secondary endpoint of overall survival.

These patients had a baseline PSA of 16 to 18. The prior taxane chemo, similar to the previous trials, roughly one-quarter of the patients, prior ARPIs in 6% of the patients. We could see on the right in the Kaplan-Meier curve the primary endpoint of radiographic progression-free survival and the overall cohort was not reached for the combination versus 22 months in the control arm, which was a hazard ratio of 0.63, 95% confidence interval of 0.51 to 0.78. In the HRR mutation patients, 28 versus 16 months, in the non-HRR mutation patients, also significant, hazard ratio of 0.66, p-value, 0.009. With 31% overall survival data maturity, no overall survival benefit to date.

This is a recent publication by Fizazi and colleagues in Nature Medicine. This is 2024 updated results. Continued RPFS benefit, hazard ratio of 0.45, and perhaps a trend toward overall survival benefit in the HRR-mutation cohort. The overall survival not reached in the talazoparib plus enzalutamide arm versus 33.7 months in the placebo plus enzalutamide arm. The hazard ratio is 0.69, so we do see a signal there, but 95% confidence interval, 0.46 to 1.03.

To summarize these studies and the recommendations by the NCCN in 2024, we see that olaparib and rucaparib monotherapy are preferred regimens for BRCA-mutation patients with evidence of disease progression on prior NHT and no prior docetaxel. Additionally, olaparib monotherapy may be useful for patients with HRR mutations other than BRCA1/2, and olaparib monotherapy may also be useful for HRR mutations with progression on prior docetaxel and NHT. Finally, rucaparib monotherapy may be useful for BRCA mutation patients with progression of prior docetaxel and novel hormonal therapy.

When we look at the summary for the combination, we see here this is a take-home slide showing the indications for each of these, and we look at olaparib plus abiraterone for BRCA mutation. This is for patients with no prior docetaxel or NHT or prior docetaxel, no prior novel hormonal therapy. For niraparib plus abiraterone for BRCA mutation patients, this is approved for no prior docetaxel or NHT, prior docetaxel, no prior NHT, and prior NHT and no prior docetaxel. Finally, for talazoparib plus enzalutamide for HRR-mutation patients, this is recommended for no prior docetaxel or NHT, prior docetaxel and no prior NHT, and finally, prior NHT and no prior docetaxel.

We thank you for your attention for this NCCN update, the most recent 2024 updates, focusing on, specifically, changes to the PARP inhibitor recommendation. We thank you for your attention.