Zachary Klaassen: Hello, and thank you for joining us for this UroToday discussion of key updates to the NCCN Prostate Cancer Guidelines. This is from version 1.2023, which is published in September 16th, 2022. Today, we're going to be discussing systemic therapy for mCRPC, specifically several key PARP inhibitor updates to this most recent guideline.

My name is Zach Klaassen. I'm an assistant professor in the Division of Urology at the Medical College of Georgia. And with me today is Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto.

So with regards to disease progression on ADT, most men treated with ADT for advanced prostate cancer will progress to castration resistance. And this entity called castrate-resistant prostate cancer is secondary to progressive disease, either clinically, biologically, or radiographically, despite castrate levels of testosterone.

So there's important next steps when men reach this point. And for men with progression on ADT, there's several items we should entail. The first one, is confirming a castrate level of testosterone. The second, is intermittent imaging to monitor for metastases. And this can be individualized by patients' cancer risk, age, overall health, PSA velocity, as well as other factors. Importantly, even in these men that have progressed on ADT, we should continue androgen deprivation therapy. For men with metastatic CRPC, there's additional follow up and workup that is recommended, which may include metastatic lesion biopsy, MSI or MMR testing, as well as germline or tumor testing for HRR genes.

So today, we're going to delve into a little more of the treatment for mCRPC. As you can see here, this is the systemic therapy for mCRPC, as highlighted in the most recent guidelines, and it's quite the potpourri of options. If we look at the top left, there's recommendations for no prior docetaxel, and no prior novel hormonal therapy. And the bottom left is prior docetaxel, no prior hormonal therapy. In the top right, we have recommendations for prior novel hormone therapy, with no prior docetaxel. And in the bottom right, we have recommendations for prior docetaxel, and prior novel hormonal therapy.

What we can see here highlighted is that olaparib is useful in certain circumstances for patients that have had prior novel hormonal therapy and no prior docetaxel, as well as those that have had prior docetaxel and prior novel hormonal therapy.

So one of the key recommendation changes from this most recent guidelines is as follows. Olaparib is a treatment option for patients with mCRPC and a pathogenic mutation, either germline or somatic, in homologous recombination repair genes, as you can see listed here, including BRCA1, BRCA2, and ATM, who have been treated with previously androgen receptor directed therapy. Importantly, and this is the key update, is that efficacy appears to be driven by the cohort of patients with at least one alteration in BRCA1, BRCA2, or ATM. And in particular, by patients with BRCA2 or BRCA1 mutations, based on exploratory gene-by-gene analysis. Additionally, there may be heterogeneity to response to olaparib for non BRCA mutations, based on the specific gene mutation. And this is what we're going to dig into and explain further today.

So just a quick review of PARP inhibitors. These are oral agents that exert their activity through the concept of synthetic lethality. And currently, there are two PARP inhibitors approved by the FDA for use in prostate cancer, and this includes olaparib as well as rucaparib.

The key trial that led to the approval of olaparib was the PROfound study, which was published in New England Journal of Medicine in 2020. This was a Phase III trial of olaparib BID, versus physician's choice of either abiraterone or enzalutamide in mCRPC patients, with progression on at least one NHA, and up to one prior taxane.

These patients were required to have a somatic or germline HRR mutation. There were two cohorts in this trial. Cohort A was made up of BRCA1 or 2, or ATM mutations. And cohort B was made up of one of the other 12 HRR gene mutations that were tested for.

Inclusion criteria for this trial included men age 18 years or older, metastatic CRPC, progression on previous abi or enza for non-metastatic CRPC, or metastatic castrate-sensitive prostate cancer, ongoing ADT with the previous taxanes being allowed as part of the inclusion criteria.

For this trial, they used a biomarker assay to develop these cohorts. This was an investigational assay, based on FoundationOne CDx. And that the goal of this assay was to identify alterations in one of 15 pre-specified genes involved in homologous recombination repair, including BRCA1 and 2, ATM, as well as several other mutations that we're familiar with, including CDK12, CHEK 1/2, PALB2, as well as the other RAD51 you can see listed here.

I'm going to hand it over to Chris, who's going to walk us through the results of PROfound, including some important gene-by-gene analysis.

Christopher Wallis: Thanks, Zach. So here, we're summarizing the data from the first publication from the PROfound trial, looking at imaging based progression-free survival. And you see in the overall study cohort, this is among patients with any of the 15 HRR gene mutations, that there's a significant improvement in imaging based progression-free survival for patients receiving olaparib. And the hazard ratio here is 0.49.

Importantly, we see stratification. And so cohort A, again, composing those patients with BRCA1, BRCA2, or ATM mutations, has a fairly substantial benefit here with a hazard issue of 0.34. Whereas, the remainder of patients in cohort B, with other HRR alterations, do not derive a significant benefit. And you can see here, the hazard ratio 0.88. And this comes from the supplement of this first publication from PROfound.

As we move forward, we then saw the second report of the PROfound trial, looking at survival as the endpoint, rather than progression-free survival. And again, in cohort A, we see a splitting of the curves in a significant difference in overall survival, that has ratio of 0.69. However, in cohort B, we see no significant benefit. The hazard issue here is 0.96. And so, it's really clear that there's differences in the benefit of olaparib, on the basis of the HRR gene mutation. And while FDA approval is based on 14 different potential gene alterations, it's clear that patients may not have the same benefit of this treatment approach.

And so, one of the first reports of this comes out of the supplement again, of the survival analysis from the PROfound trial. And you can see here, fairly substantial variation in many of these gene alterations are so infrequent that the authors weren't able to calculate hazard ratios. But we see a real benefit among those patients with BRCA1 and BRCA2. So not just cohort A, but a subset of cohort A. And in fact, when we look down towards the bottom here, at PPP2R2A, we actually see a harm. And so, the NCCN guidelines have not recommended olaparib in patients with this specific HRR gene alteration.

Moving forward, we've seen even more data come out. And so this is a gene-by-gene analysis of overall survival in patients with alterations in just a single gene. Obviously, some patients will have multiple mutations. And we have at the top, the most frequent alterations, and the rarer ones towards the bottom. You can see that BRCA1 and BRCA2 patients appear to derive substantial improvement in the overall survival duration. Whereas, others are less clear. And we can see, obviously here at the bottom, RAD54L suggests a really big difference, although this is infrequent alteration that we're unable to calculate a hazard ratio.

And when we put it a different way, and this again comes out of a supplement, we can see that in non BRCA genes, so that's cohort B as well as the ATM patients, we don't see any benefit to the use of olaparib. And when we look at ATM specifically, again, there's no benefit with a hazard ratio of 0.93 here. And CDK12, which is again, a fairly common alteration, we again see no benefit to olaparib over the control.

We got some updated data in 2021, which again, are part of the update study guidelines here. And you'll recall, the cohort A is BRCA1, BRCA2, and ATM, and we see that improvement in RPFS, with a hazard ratio of 0.34, and in OS with a hazard ratio of 0.69. But when we look at the specific BRCA1 or BRCA2 subset of that, the RPFS hazard ratio drops to 0.22, and the OS hazard ratio drops to 0.63. Whereas, in the at ATM subset, we see no significant benefit, and really no benefit at all to the use of olaparib over control. And so it is this a really defined subset of patients with BRCA1 or BRCA2 alterations that appear to derive the greatest benefit.

And we can add a little more nuance to this, potentially. And again, these are data from the supplement of the survival paper, and you can stratify by receipt of prior therapy. And so, you'll recall that in PROfound, all patients had to have progressed on a prior angio receptor, a targeting agent, either abiraterone or enzalutamide, and they could have, but did not have to have, received prior taxane. And so, if you look at the stratification, according to received prior taxane, among those patients with ATM mutations, those who received a second angio receptor targeted agent did nonsignificantly better than those who received olaparib. But it was a bit reversed in those who had received prior taxane. And similarly with CDK12, we saw better responses, although again, not statistically significant in those who had not received prior taxane, for those receiving olaparib. Whereas, if you had received prior taxanes, that benefit disappeared.

And so, there's a little bit of additional nuance, I think, we can bring to this discussion, rather than just saying that olaparib or PARP inhibitors are beneficial with patients with homologous recombination repair defects. But there's clearly, differences between patients on the basis of which gene is altered, and even within specific alterations on the receipt of prior therapy.

And so, as we sort of try to transition to clinic on Monday and look at our practice, we need to consider alternatives. And so, this is just one idea here, and this is an indirect comparison, using the data from PROfound and CARD, to consider, what would've happened if we used cabazitaxel instead?

And so, you can see in cohort B, you know what we can use based on aggregate data. There's a real suggestion that we may get benefit in both OS and RPFS, if we use cabazitaxel instead of olaparib.

And put a different way, if we look at the probability that this is the best treatment approach. And probability that cabazitaxel will be the right thing to do for patients fitting that cohort B definition. Is over 75%. And so I think, we should consider in chemo eligible patients at least, these alternatives, and really focus our use of PARP inhibitors in those patients who are most likely to benefit.

And so, as we come back to the specific guideline recommendations from the NCCN panel, there's an acknowledgement that olaparib is approved in patients with a wide number of HRR gene alterations. However, the efficacy really is driven by patients with BRCA1 and BRCA2 mutations. And so, these are the patients who I think are most likely to benefit. And if we're using olaparib outside this subset, we really can expect a heterogeneity of response and honestly, probably a poor response for many of these patients.

And so, as we come to close the NCCN guideline panel recommendations, in terms of the role of olaparib in mCRPC, are to consider its inclusion as a treatment in patients who have identified HRR mutations, and have progressed on prior angio receptor directed therapy, with or without receipt of prior docetaxel. However, we can anticipate significant heterogeneity benefit, and predominantly expect efficacy in patients with at least one alteration, and particularly, those with BRCA1 or BRCA2 mutations.

So I thank you for joining us, and hope that this update on the role of PARP inhibitors in mCRPC, based on the most recent NCCN prostate cancer guidelines, has been useful to you.

Thanks again.