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PARP Inhibitors and Immunotherapy in Prostate Cancer


Kristie L. Kahl: Dr. Concepcion, can you talk about some of these new therapies that were approved in 2020?

Raoul S. Concepcion, MD, FACS: There has been a lot of advancement in the whole management and approval of agents in advanced prostate cancer, let's just start there. And I think it's important for our viewing audience. When we talk about prostate cancer, whether it's localized or whether it's advanced, I think we need to be very specific on the type of patient that we're discussing. Because again, I think that the therapies, whether it's in surgery, radiation, active surveillance in the localized space, or whether it's in the advanced space, all the trials, all the therapies, all the indications depend upon the particular phenotype we're discussing.

For localized prostate cancer, I think we need to be discussing patients as they fall into NCCN risk stratification. So, they're either very low risk, low risk, favorable intermediate, unfavorable intermediate, high risk, and very high risk. Depending upon the risk stratification, we will determine what options are available to you. And as we know, in the localized prostate cancer space, especially very low risk and low risk, we should be utilizing and talking to our patients about active surveillance, which is not appropriate in the unfavorable intermediate or high-risk patients. So that's why we need to be very specific when talking about low risk or local prostate cancer, or the advanced prostate cancer space, which I define as anybody that you're thinking about starting androgen deprivation therapy.

Historically, in the metastatic castration resistant prostate cancer space, which used to be known as M1, we've pushed back a little bit to this arbitrary designation of M0 or nonmetastatic castration resistant prostate cancer. Over the past five years, there has been a market change in the paradigm and the therapeutics in the metastatic castration-sensitive prostate cancer space. But we have patients in the nonmetastatic castration-sensitive prostate cancer space, which historically has the biochemical failures. When we focus specifically on castration-resistant prostate cancer, most of the last decade, we saw a slew of agents that were approved, whether they be androgen receptor targeting agents, or synthesis inhibitors as receptors or receptor antagonists; autologous immunotherapy; alpha emitting radiopharmaceuticals; and taxane therapies. Once (those therapies were) flushed out, we really didn't see a whole lot. but over the past couple of years, we've seen all those agents now get approved in a much earlier phenotype. So initially, all of those mechanistically different agents were approved in metastatic castration-resistant prostate cancer. Now, some of those agents have been approved in the nonmetastatic castration-resistant prostate cancer. That entire nonmetastatic castration-resistant prostate cancer space may completely go away as we utilize molecular imaging. So, we've seen a push towards some of these agents earlier in the disease, primarily the nonmetastatic castration-resistant prostate cancer space. And that's been over the past couple years. We've seen therapeutic regimens change for the metastatic castration-sensitive prostate cancer space, that's either patients that present with de novo metastatic disease, or patients that progress beyond definitive therapy. But it's only been this past year where we've had finally a newer mechanistically different newer agent that finally has been approved for metastatic castration resistant prostate cancer.

Christopher M. Pieczonka, MD: I think that this whole thing is about precision guided therapy. Having been in practice now, for the better part of 20 years, I've seen the era of giving everybody some sort of hormonal agent and probably a lot of it was used inappropriately. I think that the paradigm is shifting to (doing somatic tumor testing). We're going to look at the biology of the tumor, we're going to look for whether or not you have hereditary cancer inheritance, and we might have a lock in a key for your disease. So that lock and key has come about with things that are called PARP inhibitors.

We now know that patients have some sort of deleterious DNA repair gene abnormality, and that's a basket of multiple genes. The one that has the biggest claim to fame are BRCA. Those patients have been shown, without any doubt, that usage of these PARP inhibitor therapies, specifically olaparib (Lynparza) and rucaparib (Rubraca), are of benefit in that disease space. So, they're a little bit different in a labeling indication, the labeling indication for Lynparza is pretty broad based. And that is inclusive of anyone who has catrate-resistant prostate cancer and has failed some sort of novel hormonal agent. If those patients have some sort of deleterious mutation, it's really a pretty provocative improvement in overall survival. What needs to be worked out is which genes have the best survival? As you look at that gene pool, is the BRCA mutation better than the CHEK or ATM mutation? We're beginning to understand that, but it's another tool we have in our toolbox.

Another tool that we have in our armamentarium is the possibility of checkpoint inhibitor therapy. Checkpoint inhibitors are immune stimulating agents, for lack of a better term. There's a lot of buzz on that in the urology world. We have a potential indication that's really based on patients who have precision-guided therapy. You're going to look at their tumor mechanism, see if they have some sort of mismatch repair, see if the patients have a high tumor mutational burden. As we start to embrace these checkpoint inhibitors, it’s very exciting times in terms of these new approvals for these new drugs. And just like anything in life, once you get approval, then the pharma companies drive that approval earlier and earlier in the disease.

Raoul S. Concepcion, MD, FACS: Chris, I think you make some really great points. The big point is when you start looking at PARP inhibition, and it is critical that in order to really understand how this drug works, you have to understand DNA damage repair. So basically, all of these pathogenic variants and mutations really are happening in DNA damage repair genes, which is sort of a broad category. When you have DNA damage repair genes, you really have 2 different types of pathways. You have homologous recombination, which is BRCA1, BRCA2, and ATM checkpoints; and you have the DNA mismatch repairs, which are single stranded breaks in a number of genes, including MSH1. You also have to look at microsatellite instability. And it's important to understand the difference of what makes a tumor MSI-high. Now all of a sudden, you have neoantigens that get manufactured by these tumor cells, which makes them more immunogenic. So to Chris's point, the concept, especially as we move further and further along down this progression of heavily treated CRPC patients…what we as urologist need to start looking at is obviously an understanding of the molecular drivers and understanding of the DNA damage repair pathways, but more importantly, what testing should we be ordering when the patient progresses? Should is be somatic or germline?

Our understanding of potential germline mutations is now relevant in prostate cancer, and I'll let Chris address the newer approval this year, as it went along with the approval of PARP inhibitors, is this concept of liquid biopsy. But you also have some other tests out there, which are androgen receptor variants – the AR-V7 assay, which is a circulating tumor cell assay. Once a patient starts to progress, you need to be thinking of a whole battery of tests that will include or preclude what your next line of therapy is, not just focusing on 1 particular therapy, because then you're going to potentially lose out on some other therapeutics that the patient may benefit from.

Christopher M. Pieczonka, MD: I completely agree. I think that the era of managing hormonal manipulation to treat the cancer is going to be just 1 chapter in the life story of this prostate cancer patient. I think hat a lot of urologist are comfortable with injectable therapy, but few are comfortable with oral, antihormonal therapy and even fewer are going to be comfortable with these real chemotherapies. For a lot of us that are passionate about this, we want to help our colleagues be educated about retaining these patients. And the reason why, quite honestly, is that we're converting this disease from what was uniformly fatal a couple of years ago into something that becomes more chronic.

These patients who are failing on novel hormonal therapy are still pretty healthy, and they still want to see their urologist. Part of that is becoming comfortable with these newer drug indications. Pandora's box is going to be open with all these additional precision therapies that are available for other disease states. It's a really kind of exciting time for us. And I think our job as the clinician-scientist is to be able to communicate that to our physician urology colleagues in a way that they can understand and be able to use these drugs. Because if you're not doing the molecular testing, if you're not looking under the covers, you're going to miss the potential benefit for the patient. You have to be following the guidelines for these genetic tests. And these are all new in the NCCN. If you have a patient who has high risk disease, you might consider doing some of these hereditary tests.

According to the NCCN guidelines, patients with metastasis ought to have somatic tumor testing done. So that's just a complete paradigm shift for us. And it's been made a little bit easier, because we have the availability of looking at circulating tumor cells rather than biopsies for that. It's a pretty intriguing time for us. I think once the real world comes back post-COVID, and we have the ability to get together in rooms, educate ourselves, that in the next year, hopefully, this is going to be really hot topic.

Raoul S. Concepcion, MD, FACS: Chris, I think you make a really excellent point. At the last live meeting I went to, my friend Dave Patterson, who's the chairman of urology at Vanderbilt talked about toxicity in the face of therapeutic side effects. The point that you made earlier is that many patients, even though they've blown through 2 or 3 lines of therapy, many of these patients still maintain a great quality of life and they want to maintain that quality of life.

There is also financial toxicity. For example, CAR T-cell therapies could be approaching $1 million dollars. This is kind of unsustainable, so we need to think of toxicity, not just as what the drug does to the patient, but the maintenance of quality of life for these patients as well as the financial toxicity. And again, as some of these agents get older, we know that there are some other potential more suitable, maybe even potentially more patient-friendly agents out there that we could be utilizing, especially in the in the area of androgen receptor targeting agents.

Christopher M. Pieczonka, MD: The hot button topic with thesee expensive and Part D drugs are patients feel the heat on that because, again, it's not billed directly to Medicare, like the injectables are. In the last couple of years, we've seen 1 of the drugs go off-patent. So the drug called Zytiga, which is the traditional form of medicine called abiraterone, the generic went off patent. And there's a generic availability now. And, you know, I think for a lot of us, we thought, well, this is going to be great, it's going to be easily accessible, we're going to be able to get it easier, it's going to be dirt cheap, and that's really far from the truth.

In the real world, using the generic means a couple things. One, there's effectively no payment assistance; there's no sort of pharma backing on that because it's generic. There's no educational support of any sort. At least in my practice, I rely heavily on my industry partners to provide me information to then provide to patients, like getting a website and looking at it. Using those resources makes my job easier.

There is a formulation of abiraterone that is micropolymerized, called Yonsa, and it was really manufactured to try to harness the benefit of trying to take abiraterone, which we know has benefit in CRPC patients in a way that's easier for the patients. Getting back to complains, there’s the financial aspect and also the aspect that it is easier for the patient to take. So when you take generic abiraterone, quite honestly, it's a pain. It's difficult because you have to take it on an empty stomach. And, you know, for a lot of patients, there's pill issues. They take all their pills in the morning with breakfast, and then you've got another sort of additional set of pills that need to be taken on an empty stomach. And really the advent of this drug is that is was formulated in such a way that it can be taken with or without food. From a compliance standpoint, at least in my practice, I've found that to be much easier, and I've really leveraged my relationship with the manufacturer to try and get patient assistance. So when a patient has a generic, there's no one out there to help them besides my own staff. So I want to be able to if I decide a patient has to go on a drug, to give it to them without having to fight a ton of fights on that. Raoul, what are your thoughts on this micronized version of abiraterone?

Raoul S. Concepcion, MD, FACS: Yonsa was quietly approved. We’ve been looking at this drug for a couple of years, and there are clearly some inherent advantages of this micronized formulation. Chris, you bring out a great point that when the original abiraterone acetate went generic and these generic companies were lining up, 1 thing that patients depend upon or practice depends upon is pharmaceutical manufacturer support. It's important to understand that Yonsa not a generic drug, it is a branded drug. And so Sun Pharmaceuticals can actually give your practice support very similar to any other branded drug that we're using.

When you look at the data, relative to areas under the curve bioavailability, because of this micronized formulation, which allows for better absorption and, therefore, better levels within the bloodstream, they're able to use a lower dose, which potentially has its benefits. With Yonsa, there is a lower dose; you don't have to worry about food and the variability with or without food; and the plasma concentration is relatively stable.

When you look at the androgen receptor antagonists, it's sort of the same story. We have enzalutamide (Xtandi) and apalutamide (Erleada), which are receptor antagonists, but we also know that there is a significant fatigue factor and potentially a seizure risk with those 2 agents. Now, a little bit mechanistically different but still a novel hormonal therapy is darolutamide (Nubeqa), which we believe, has less of a fatigue factor. So as we take into account the quality of life issue, these things all have to be taken into consideration when talking to a patient

To your point, Chris, which is why I think that people have moved these oral agents up into the whole cascade, is people would rather take an oral pill as opposed to an injection. That's why it's going to have its advantages as an LHRH antagonists, because it's a pill. But I think it's important for the audience, if you're going to treat advanced prostate cancer, you can't pick and choose which 1 of these agents you're going to deliver. You have to be willing to give all agents whether it's pills, injections, radiopharmaceuticals, because they all will be part of the potential therapeutics out there as these patients progress and develop resistance mechanisms.

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