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Fred Saad: Welcome to Uro Today and our online medical education program, Beyond Adjuvant Blockade: to New Pathways and Novel Treatments for mHSPC and mCRPC. I'm Fred Saad, and I have the honor of moderating today's discussion following a presentation by Dr. Neal Shore, a close friend and colleague over the last 25 years. His topic is going to be PARP Inhibitors - Targeting DNA Repair Pathways. Dr. Shore, it's all yours.

Neal Shore: Well, thank you very much. PARP inhibitors are a new and important oral therapy for our patients with advanced prostate cancer, and my charge will be to talk about, briefly, the mechanism of action of why PARP inhibitors matter now as monotherapy, as well as in combination. What are the approvals?

But very importantly, the role of genetic testing is integral to understanding why PARP inhibitors have come into importance within prostate cancer. Of note, they're approved in breast cancer, ovarian cancer, and pancreatic cancer. But we're going to focus on prostate cancer today. And I think at the very end, we've had a plethora of really important trials both in mCRPC monotherapy and also in mCRPC combinations. One has to ask, are there differences among the PARPs, and how do you make these selections?

This is a busy slide, but it's important to recognize that we've had so many great advances, and throughout the beginnings of patients with high-risk localized disease, to biochemical recurrence, to mHSPC, whether low volume, high volume, nmCRPC, but particularly in mCRPC, an area where the clock or the timeline of the aggressiveness of the phenotype starts to really move forward very quickly.

Going back to 2004, we saw taxanes and then in 2010, sipuleucel-T, but now, 14 years later, we see all these other therapies. Today, we're going to talk about the importance of PARP inhibitors and why they matter as an additional part of our toolbox, our armamentarium, with taxanes and radiopharmaceuticals, as well as androgen receptor pathway inhibitors, and other immunotherapies. It's a very exciting time. Ultimately, we want to prevent cause-specific prostate cancer mortality.

So I think it's not always the easiest thing to understand why PARP inhibition works. But if we look at this schema here, one sees that PARP activity, on the far left of the slide, facilitates DNA repair. And the androgen receptor, underneath that first schematic, is important because it also helps bind damaged DNA through PARP activity. So there are multiple pathways, but at the end of the day, DNA repair, when done correctly, is ideal, but repairing damaged cells is the challenge.

So if you move to the right side of the schema, PARP inhibition and trapping, as it's sometimes called, on damaged DNA in addition to adding an ARPi, or an androgen biosynthesis inhibitor in this case, we're using the novel hormonal agent abiraterone, there's a reduction of AR androgen receptor protein levels, and prevention of DNA binding and repair. Ultimately, it's the increase in DNA damage pathways and anti-prostate cancer activity that we are trying to accomplish. So that's the synergy for the rationale.

Now, this is a busy slide, but it's important to recognize that there have been really breakthrough series of both Phase II and Phase III trials in mCRPC that have looked at PARP inhibition as monotherapy. And we now have multiple; here we're listing four different PARP inhibitors: olaparib, niraparib, talazoparib, and rucaparib, and various Phase II and Phase III trials.

One, it's important to recognize that, given their Phase II or Phase III nature, there are different endpoints. There have been some differences in the gene panels, and you can read through these. But I think it's important to recognize that if we're looking at a homologous recombination repair mutation panel, one needs to be testing in order to be thinking about the approved indications, and that's a very important consideration.

So when we talk about DNA damage-repair mutations, and that subsumes the homologous recombination repair as well as other DNA damage-repair pathway alterations, such as MLH and MSI high. Really, very nice seminal work published in Cell by Robinson informed us, or taught us, that almost a quarter of patients with mCRPC will have a DNA repair pathway aberration. And this is very, very important, because it can vary from 20 to 30%, depending upon your demographic and where you are in the world. But this is a pretty well-inculcated number.

So almost 25% of patients with mCRPC will have an alteration that can benefit from an HRR-approved therapy, such as a PARP inhibitor, or even potentially, the tumor agnostic indication for MSI high MLH patients, and that would be in the form of pembrolizumab.

Now, to the right, we see germline. The somatic and the guidelines suggest checking all of these patients who have resistant disease, and we'll talk about how you can ascertain their alteration in a minute. But then there's the germline, or the germline, which is really the hereditary risk you receive from either the egg or the sperm from your parents. This very nice work published by Pritchard for metastatic patients suggests 12% of patients have a germline alteration.

So, a couple of important points here. Almost half of those will have BRCA2, and that becomes very important as we talk more about some of the findings we've seen in our survival benefits. But if you look at germline, upwards of 12% with metastatic, and if you look at all of our patients who have high-risk localized disease, data would suggest 5 to 7% of patients will also have a germline alteration. So you may say, "Well, that doesn't seem like a lot," but that 5 to 7% is extremely important, as it can impact not only the patient but also what's known as cascade family testing. So, helping inform the patient of his children, nieces, nephews, and siblings of their risk for not only potentially prostate cancer but other cancers such as breast, ovarian, upper tract, urothelial, and pancreatic cancer.

So how do we check? We can check for germlines; it's really pretty basic. It's a blood test, and you see that on the far right. Or it can be even a buccal smear or saliva. Now fortunately, the cost for doing germline testing has decreased dramatically over the last decade and a half. It's down to just a couple of hundred US dollars. Now in developing parts of the world, that still is a lot of cost, but it is getting more accessible.

Now, the somatic testing can ideally be obtained from tissue, archival tissue from prostate biopsy or prostatectomy, or metastasis-directed biopsy. Now, if the tissue is not available, not ascertainable, or degraded, you can get blood-based testing, or what we sometimes call a liquid biopsy. And one of the key take-homes is, if you just stopped at germline for your metastatic patients, you would miss up to 50% of additional HRR mutations. So that's very important in terms of your pathway.

A seminal paper that was published in the New England Journal, and led by our dear friends and colleagues, Johann de Bono and Maha Hussain, was the PROfound trial, a Phase III trial that ultimately led to the approval of olaparib as a monotherapy. Approval has been received fairly globally at this point in time. But ultimately, these were mCRPC patients who had all progressed on a novel hormonal agent, and a significant percentage had also received taxane-based therapy, although it was not a requirement to be part of the trial.

Two different cohorts. Cohort A was just the BRCA1, BRCA2, and ATM, largely based on earlier Phase II studies, and Cohort B was another 12 HRR mutation alterations. Patients were then randomized in a two-to-one fashion, to receive in both cohorts either olaparib 300 milligrams twice a day, versus the physician's choice, which was really another way of going if they had received abiraterone, then they'd receive enzalutamide or vice versa.

The primary endpoint was RPFS. A key secondary endpoint was overall survival. And this was a BICR trial, which means Blinded Independent Central Radiology.

I'll go right to the Kaplan-Meier, and one can see a really rather dramatic impact on the RPFS in Cohort A. Again, that's BRCA1/2 or ATM, and a hazard ratio of 0.34. And I think this is really extremely impressive. If you take out the ATM, that hazard ratio decreases to 0.22. This is quite a remarkable accomplishment of this particular study. We also went on in that trial to show that there was an OS benefit, particularly in Cohort A of a rather dramatic proportion, particularly in the BRCA patients.

A follow-up trial called the TRITON-3 with a similar population. Again, these patients, though, had to be chemotherapy naive, and these looked at patients who were BRCA or ATM. And of course, they would've had a prior novel hormonal agent, or androgen pathway inhibitor, as the acronym they used here.

And this is a really interesting trial, an important trial also subsequently published in New England, where patients were randomized to another important PARP inhibitor known as rucaparib, 600 milligram BID, versus a physician's choice, docetaxel, abiraterone, or enzalutamide. Now, this was really the only head-to-head trial that we have seen to date looking at a PARP inhibitor going against docetaxel. And the endpoints, primary and secondary, are listed. And this was a successful trial.

And you see the Kaplan-Meier curve here. And particularly, I think this was very provocative, and really gave corroborative importance to the role that PARP inhibitors play, particularly in patients with BRCA alterations.

So, what we have found after these two important trials, PROfound and rucaparib, is that PARP inhibitors are effective as monotherapy in our mCRPC patients with patients who have HRR alterations.

Now, why do I say that as opposed to BRCA alone? Because the FDA approved 14 of the 15 HRR alterations in PROfound, and that was approved for monotherapy olaparib use, and that approval exists today in 2023. A more limited approval by the EMA, just for cohort A, the BRCA patients and ATM, rucaparib has also received approval. Unfortunately, it's not readily available as the purveyor, the provider of this drug, has not proceeded right now with wholesale commercialization.

Now, genetic testing is absolutely key, because how can you think about precision-based therapy, as it informs not only progression, but also prognosis? Overall survival clearly is impacted, particularly in the BRCA patients. There's data that supports the fact that even BRCA patients who you're monitoring with localized disease, and even potentially with active surveillance, would require a more aggressive form of surveillance.

So, it's very clear now that if you have a patient with a BRCA alteration, they get a tremendous benefit. But patients with other HRR alterations, who are smaller in their prevalence, we're trying to continue to go forward and understand the role for other HRR mutation patients. And I think this is very, very important, and somewhat controversial, but it certainly is important regarding shared decision-making discussions.

So, that brings us to a very important trial led by my good friend and colleague, Fred Saad and Noel Clarke, called the PROpel trial. And this was an approximately 800-patient trial, patients at mCRPC. And this was first-line, so the absolute, really, majority of these patients had only received monotherapy ADT, and then developed first-line mCRPC, if they'd received abiraterone or other NHAs, you see the criteria. A one-to-one randomization, stratification factors listed. Primary RPFS endpoint, and the secondary, alpha-controlled overall survival.

Here's the Kaplan-Meier, which demonstrates that in the patients who had the BRCA mutation, the curves separate early and incredibly widely in the combination of olaparib and abiraterone versus just abiraterone and placebo. Now, this was an active control. This was not against a pure placebo. And this is rather dramatic, this difference in RPFS benefit. The overall survival benefit is trending positively, but has not yet reached statistical significance.

That moves us to TALAPRO-2, another very similar trial designed to PROpel, but in this trial, a different PARP inhibitor, talazoparib, and a different androgen receptor altering drug enzalutamide, rather than abiraterone. And again, approximately 800 patients. There are some slight differences in the gene alteration panels chosen. Similar primary and secondary endpoints. And this is like the PROpel trial, TALAPRO-2, and this is very important, was an all-comers population. And separately, later on, we looked at HRR alteration results. But this, both PROpel and TALAPRO-2, were the all-comers mCRPC population.

And likewise with PROpel, what one sees in patients who had HRR deficiency, and particularly also a rather dramatic and robust impact on the BRCA patients, is once they see the hazard ratio here for those with an HRR alteration, or deficiency as it's described here, of a hazard ratio benefiting the combination versus monotherapy enzalutamide, again, in active control. Now in both of these trials, PROpel and TALAPRO-2, there were a percentage of patients that were either non-deficient or unknown.

And then the third trial of importance now is MAGNITUDE. It's a little bit more of a complicated schema. I'm not going to present it here for time purposes, but suffice it to say that MAGNITUDE, looking at niraparib and abiraterone, also showed an RPFS benefit for the BRCA subgroup, with a hazard ratio of 0.53, and survival also still pending additional approval.

So how do we interpret these data? We're suddenly, we've seen now in the US, the FDA has, as of the end of the summer of 2023, approved accommodations for olaparib and abiraterone for BRCA gene alterations. They've also approved it for niraparib and abiraterone for BRCA alteration. In TALAPRO-2, the enzalutamide/talazoparib combination has been approved for their nine-gene panel. Now interestingly, these other combinations, based upon TALAPRO-2 and MAGNITUDE, are only approved as combinations. Olaparib is approved as monotherapy for a 14-gene panel, and also approved in combination as first-line with abiraterone for mCRPC.

In the EMA, the approvals are somewhat reversed. For PROpel, it's the combination by EMA was approved in the all-comers population for combining olaparib and abiraterone, with or without gene panel HRR mutation findings. So somewhat conflicting approvals, and differences additionally conflicting, as it relates to PROfound. So this creates some level of confusion.
I think the first bullet here, the BRCA mutation patients, the hazard ratios are virtually comparable for PROpel and TALAPRO-2. In MAGNITUDE, it was a little bit higher. Again, with the caveat that we don't have head-to-head comparator trials.

There are some discrepancies. Clearly, we see an RPFS benefit in both PROpel and TALAPRO-2 in the non-BRCA population. Not in MAGNITUDE, as that group was removed from the study schema early on by the Data Safety Monitoring Committee.

So there is some information here regarding testing, as you can see outlined by percentages regarding valid tumor test, or circulating tumor DNA tests. I think that's important, and important to consider for your ongoing genetic testing.

At the end of the day, are there differences in tolerability and safety profile? I would say there are, but we don't have direct comparator trials. And that could inform you on your choice of PARP. It could inform you on your choice of an androgen receptor pathway drug, especially when you're considering combinations.

And very importantly, as more and more patients are moving in the mHSPC population to resistance, we'll have seen doublet or even triplet therapy, or patients who may have received NAR pathway drug in nmCRPC. And we may start to see more patients getting combination therapy, even in the biochemical relapse population, based on the recent data from EMBARK. Other practical considerations will be pill counts and lab monitoring, and of course, cost and accessibility to therapy.

So with that, let me stop and thank you very much for your attention.

Fred Saad: Well, thank you very much, Neal. That was a great overview on a very complicated era or area that we're working on. And obviously, anybody who's interested in this will have to dig a little bit deeper because...

So maybe a couple of questions, because obviously, you went through the combination data quite quickly. And as you mentioned, for both olaparib and abiraterone, and talazoparib and enzalutamide, the data, in terms of primary endpoint, which was, and we have to remember is an RPFS, so radiographic progression-free survival. These two trials are clearly very positive. We're doing much better compared to the standard of care that we use today for mCRPC. And both are positive for the intent to treat population, so regardless of mutational status.

So in that situation, who would you consider for combination therapy if you were allowed to access those combinations? Because obviously, not all patients are created equal, in terms of their mCRPC status. Obviously, BRCA patients are, it would almost be malpractice not to offer something to BRCA patients. But the non BRCA patients, are there profiles that you would consider going beyond BRCA in those patients, and offering PARP inhibitor?

Neal Shore: Sure, it's extremely important important question. It's met with a lot of controversy internationally by specialty. I fall on the side of recognizing that, as you say, in the all comers population, in the intent to treat, this was a successful trial. It met its primary endpoint, full stop. Both in TALAPRO-2, and clearly in PROpel.

And so, I like to have that shared decision-making conversation. And in an ideal world, would want to have the patient, in conjunction with good explanation, make the choice, recognizing that there's clearly an RPFS benefit. OS is still early in the intent to treat, clearly unbelievably positive in BRCA patients.

And of course, when we add an additional therapy to an AR pathway inhibitor drug, there are some safety and tolerability issues, which we have to review. I didn't have time to go into that, but I think they're very manageable. I mean, there are some GI alterations, some nausea, mild diarrhea, and of course, myelosuppression has to be monitored. So, just a simple monthly CBC. But I do think that for the fit patient, to your point, with good bone marrow production reserves, who wants to be as aggressive as possible, I strongly believe in the combination, if I can get it accessible.

We have so many life-prolonging therapies, but yet still, only about 75% of our patients, we published this and look, myself and Dan George, and a group of over 2,500 patients from 2019 to 2021 in Canada and the US, only 77% received one life-prolonging therapy. And of that 2,500, 38% received a second therapy, and 18% received a third life-prolonging therapy. So the combination opportunity, as your question belies implies, is really important to me, because I want to make sure that patients can be exposed to as many novel mechanisms of action as possible, and safely.

Fred Saad: Yeah, absolutely. And I would totally agree. I mean, the data would suggest the healthier patient, younger patient. And we've got patients at higher risk, if they got chemotherapy prior to becoming mCRPC, if they have visceral metastatic disease, these patients seem to do much better. And like you say, unfortunately, many patients don't go beyond the first-line mCRPC treatment, and the next line is often chemotherapy. So if you can delay that, or even avoid it in patients who never want to go there, I think that would be a great benefit.

And so, I think these trials are the first step forward. And yes, there is controversy, but I think the case-by-case, and discussion with our patients to include them in the decision, is critically important.

So I think with that great overview, I would encourage people to dig a little deeper, because I think you tickled everybody's attention in this area that is still relatively unknown, especially for urologists. And this is an opportunity, I think, to work with our medical oncology colleagues. Again, this is probably not for everybody's taste, but those that are interested, and people like you that are dedicated to these patients, this is not rocket science. You just need to have the right structure.

So on that note, thank you very much, Dr. Shore, or Neal between us, for that excellent overview, and hope this was informative to the audience.