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Role of PARP Inhibitors in Prostate Cancer



Judd Moul, MD: Speaking of infancy, we’re getting down to some final thoughts about PARP [poly ADP ribose polymerase] inhibitors and other novel therapies, as well as lots of new trials. Neeraj, can you give us an overview of this space? From a practical standpoint, what do urologists and medical oncologists need to know now as a takeaway from ASCO [the American Society of Clinical Oncology annual meeting] 2019?

Neeraj Agarwal, MD: I’ll come to the last point first. What should medical oncologists take from ASCO 2019? There is no drug that is approved, or is going to be approved, at least until the next ASCO in 2020. Based on ASCO 2019, we don’t have any approved PARP therapies in the clinic. No PARP inhibitor is approved for clinical practice yet.

As for PARP inhibitors in general, as we know, these drugs were only thought to be applicable to those patients who have DNA defect-related genes or DNA repair mutations, either in germline or in the tumor. The TOPARP study published in the New England Journal of Medicine 2 or 3 years ago showed that patients who had BRCA1/2 and some of these other mutations respond to olaparib.

I think the field has moved toward treating patients regardless of these defects. New data have emerged in the last 1 or 2 years showing that when we use this deeper androgen blockade via enzalutamide or other drugs, that increases the lines of these cancer cells on the poly ADP ribose polymerase, or PARP, enzyme.

There are pretty strong data published now, obviously not clinical data, but preclinical and in vitro data. We don’t have human-based data, but it’s all very strong data that when we use enzalutamide in these cancer cell lines, it leads to upregulation of PARP and lines of prostate cancer cells on the PARP enzyme, which allows them to survive enzalutamide.

This newly emerged concept over the last 1 or 2 years has led to multiple clinical trials that are being connected in this area comparing novel hormonal therapy, or NHT, plus/minus these PARP inhibitors. Whether it’s talazoparib, niraparib, or rucaparib, I won’t pick up any of the trials, but this is a general concept that 3 ongoing randomized phase III trials are using.

I’ll just make 1 quick point on this. I personally believe that talazoparib is unique among all PARP inhibitors because it not only inhibits PARP as an enzyme, but also traps PARP on the DNA. So far, it is based on all preclinical data, so I do not know if it’s going to translate into higher clinical efficacy for talazoparib. I think the basic concept remains that these 2 classes of drugs together may be very synergistic, as far as prostate cancer is concerned.

Judd Moul, MD: Alicia, do you have anything else to add to that?

Alicia Morgans, MD, MPH: There remains some controversy over which DNA repair defects may be most targetable by some of the PARPs. Interestingly the TOPARP-B data were presented at ASCO. There were patients who had robust responses of BRCA1/2, which we expect and have seen in other studies. There were also some rucaparib data presented at ESMO [European Society for Medical Oncology annual congress] last year in which no patients with ATM had a response in the rucaparib trial. This ultimately led to amendments so that those patients were not being enriched in that trial. In the TOPARP-B trial that Joaquin Mateo MD, PhD  just presented at ASCO, there were patients who had an ATM mutation and responded.

What I think this raises is not necessarily that 1 drug is better than the other. We certainly don’t have that information yet, and they’ve never been compared head-to-head. Perhaps we need to be very careful about the way we identify 1 hit versus 2 hits in these DNA repair defect genes, whether they’re somatic or germline. It may matter that you have 2 hits and not just 1, and perhaps we see responses when we have 2 hits in ATM, versus having 1 hit. I think we have work to do in the basic science that supports these trials and in enriching them.

Neeraj Agarwal, MD: I want to make a really quick point. The point Alicia made was that when you are using these drugs as single agents, the purpose is totally different.

You’re looking for those mutations. They’re looking for the vulnerability inside the cancer cells from the DNA perspective, and you’re using these agents. What I mentioned was combining these PARP inhibitors with androgen receptor blockers or androgen synthesis blockers. In that case, we are not relying on underlying DNA repair defects. I just want to clarify that we are talking about 2 different concepts.

Judd Moul, MD: To follow up on what Alicia said from an educational standpoint, she mentioned the 2 hits. Hit 1 would be the hereditary mutation found in a hereditary gene, identified using a blood or sputum sample looking for a mutation that the patient inherited from a relative. The second hit would be a somatic mutation that is found in the tumor tissue or the metastatic tissue itself. What you’re saying, perhaps, is that if the patient had both a hereditary component and then they also found another mutation in the tumor itself, that could possibly at least portend a better response to some of these agents.

Alicia Morgans, MD, MPH: Particularly with ATM, but this is all speculation.

Judd Moul, MD: All speculation. Tanya, do you have any further comments on that?

Tanya Dorff, MD: I want to add a few odds and ends about PARP inhibitors and DNA repair. There are lots of great trials combining PARP inhibitors with immunotherapy. There is some interest in how that plays. There’s also a lot of work being done to show whether platinum chemotherapy—good old-fashioned carboplatin or cisplatin—are more effective in patients who’ve had these mutations. When you find one of these DNA repair mutations, it may be tempting to try to get olaparib off-label for your patient. However, if you look for a trial, you will likely access a next-generation PARP inhibitor. Who knows if it will be better, but we’ll learn scientifically while the patient is getting access to the treatment, or maybe they’ll get a combination therapy. Rather than off-label use, I promote clinical trials in these patients.

Judd Moul, MD: For urologists, myself included, this is a whole new area. I have a basic question. What’s the difference between a PARP inhibitor and a checkpoint inhibitor? They’re 2 different things, correct? Does anyone want to give a very simple answer to that?

Tanya Dorff, MD: Yes. A PARP inhibitor is usually oral. It’s a targeted therapy that is taking advantage of the fact that a cancer cell is already not able to repair DNA damage very well, and adding synthetic lethality on top of that so when the cancer cell goes to divide, it dies. A checkpoint inhibitor immunotherapy is typically intravenous. It’s an antibody, and it’s preventing the cancer from using our natural brake system on the immune cells to prevent the cancer from turning the immune system off. The idea is that your immune system might recognize the cancer, but the cancer’s very tricky and will tell it, “I’m part of you. Don’t attack me using the PD-L1 [programmed death-ligand 1] interaction.”

Alicia Morgans, MD, MPH: What’s really exciting and interesting is that there are multiple approaches to try to combine these 2 things to see if the prostate cancer traditionally not responsive to checkpoint inhibition may be responsive if we used a PARP in combination. That’s definitely a hot area of interest.

Neeraj Agarwal, MD: If it makes the urologist feel better, I do not think we know much about the DNA repair pathway and the checkpoint blockade, beyond some really early steps. We’re just starting to learn. Every year, the definition of DNA repair mutations keeps changing. Similarly, with immune checkpoint blockade, there were some major studies presented at ASCO that showed me how little I knew before then.

Alicia Morgans, MD, MPH: Yes.

Judd Moul, MD: On that note, we are about out of time. This has been wonderful. Personally, as a urologist, I have gained so much from this. You guys have been blessed to be surrounded by 3 rising stars—or are already stars—in GU [genitourinary] medical oncology. This has been an extreme pleasure. This program has been extremely informative. We thank you for joining us today and hope you found this OncLive Peer Exchange® discussion on prostate cancer to be useful and informative.

Transcript Edited for Clarity 

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