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PARP Inhibitors in Castrate-Resistant Prostate Cancer

Insights From: Daniel Petrylak, MD, Yale University; Nicholas Vogelzang, MD, Comprehensive Cancer Center
Published: Friday, Apr 03, 2020



Transcript:

Nicholas Vogelzang, MD: I want to talk about PARPs [poly ADP ribose polymerase inhibitors]. We want to spend a little time on some of the PARPs and also on some of the trials. We want to cover both PROfound, which was phase III, and TRITON, which was phase II.

Dan, we’ve talked about PARP inhibition. Where do you see this, and what’s the basis for our use of these PARP inhibitors in prostate cancer?

Daniel Petrylak, MD: There have been a number of exciting trials that have recently released data for the use of PARP inhibitors in castrate-resistant disease. The PROfound trial took those patients with DNA repair mutations, stratified them based upon BRCA versus other types of DNA repair mutations, randomized patients to receive olaparib or a dealer’s choice treatment, which could have included anything from abiraterone to chemotherapy.

They found that there was an improvement or a significant difference in radiographic progression-free survival, as well as objective response rate, in favor of those patients who received the PARP inhibitors. It’s very exciting that we’ve been able to select patients with a different molecular mutation, and then administer a drug based upon that mutation.

Nicholas Vogelzang, MD: TOPARP I think was the predecessor trial.

Daniel Petrylak, MD: Correct.

Nicholas Vogelzang, MD: This is not a big population of patients though.

Daniel Petrylak, MD: It’s about 20% of patients with castrate-resistant prostate cancer. About 10% of all patients have BRCA1 or BRCA2.

Nicholas Vogelzang, MD: Yes, and you have to do germline testing on these, or can you do it on somatic?

Daniel Petrylak, MD: You can do it on somatic as well as germline.

Nicholas Vogelzang, MD: I believe that PROfound didn’t allow cell-free DNA, or I thought they required somatic, didn’t they?

Daniel Petrylak, MD: They required somatic tissue….

Nicholas Vogelzang, MD: Or was it germline? I can’t remember.

Daniel Petrylak, MD: It was tissue that they used. There’s a difference with other studies where they’re using the liquid biopsy test to look for these particular mutations—TRITON2 and TRITON3—which are using rucaparib rather than using olaparib. TRITON2 is a phase II trial, which has about a 50% response rate in those patients who have BRCA mutations. TRITON3 is a randomized study that would of course confirm the results from TRITON2, but these are a little bit broader in their use of the molecular markers.

Nicholas Vogelzang, MD: I believe we also have a GALAHAD trial.

Daniel Petrylak, MD: GALAHAD trial.

Nicholas Vogelzang, MD: That’s coming, and that’s another PARP inhibitor, right?

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: That has not reported out yet.

Daniel Petrylak, MD: It’s not reported out yet, correct.

Nicholas Vogelzang, MD: We’re going to be dealing in this coming year probably with at least 2, maybe 3 PARP inhibitors.

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: If you’re testing early on in all patients, and if you don’t find a BRCA, or you don’t find a DNA repair deficiency, would you retest your patients?

Daniel Petrylak, MD: I do retest because this could be a clonal evolution of something that may not be picked up in the original test. I’m also excited about drugs that are trying to induce BRCA, and I think that this is going to be the next step in this particular pathway. As we said, only about 20% of patients have this mutation, but then how can we induce the cell to downregulate the DNA repair pathway such that you are sensitive to a PARP inhibitor? And this is where the combination trials are starting to come into play.

Abiraterone downregulates DNA repair enzymes. Hypoxia will do the same thing. At the ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] meeting we saw some other further abstracts looking at the combination of abiraterone plus olaparib. A randomized phase II trial showed an improvement in radiographic progression-free survival. And the interesting thing was it was irrespective of your BRCA. I think that that was a very interesting aside to this particular hypothesis.

Joe Kim, MD, at my institution has looked at olaparib combined with a drug called cediranib, which is also an antiangiogenesis agent. He demonstrated a 7-month improvement in radiographic progression-free survival in favor of the combination. Now we haven’t yet examined the different molecular markers.
 
That analysis is underway. What I thought was particularly intriguing about this case was one of my patients who happens to be a physician, and is BRCA2-positive, he was initially randomized to the olaparib only arm. He had about a 6-month response and then progressed. And the trial allowed for crossover. He went on olaparib/cediranib, he responded again. So this is again a very interesting little observation, and perhaps now we have to start looking at these combinations.

The third combination that I’m excited about is the combination of PARP plus immune checkpoint inhibitors. There is a synergy between the 2, and Fatima Karzai, MD, from the National Cancer Institute a couple of years ago presented some data of a PARP inhibitor combined with a checkpoint, and also saw the same pattern that you did not need to have a DNA repair mutation to have a response. These are ways that we could potentially expand the applicability of these PARP inhibitors to our patients.

Transcript Edited for Clarity
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Transcript:

Nicholas Vogelzang, MD: I want to talk about PARPs [poly ADP ribose polymerase inhibitors]. We want to spend a little time on some of the PARPs and also on some of the trials. We want to cover both PROfound, which was phase III, and TRITON, which was phase II.

Dan, we’ve talked about PARP inhibition. Where do you see this, and what’s the basis for our use of these PARP inhibitors in prostate cancer?

Daniel Petrylak, MD: There have been a number of exciting trials that have recently released data for the use of PARP inhibitors in castrate-resistant disease. The PROfound trial took those patients with DNA repair mutations, stratified them based upon BRCA versus other types of DNA repair mutations, randomized patients to receive olaparib or a dealer’s choice treatment, which could have included anything from abiraterone to chemotherapy.

They found that there was an improvement or a significant difference in radiographic progression-free survival, as well as objective response rate, in favor of those patients who received the PARP inhibitors. It’s very exciting that we’ve been able to select patients with a different molecular mutation, and then administer a drug based upon that mutation.

Nicholas Vogelzang, MD: TOPARP I think was the predecessor trial.

Daniel Petrylak, MD: Correct.

Nicholas Vogelzang, MD: This is not a big population of patients though.

Daniel Petrylak, MD: It’s about 20% of patients with castrate-resistant prostate cancer. About 10% of all patients have BRCA1 or BRCA2.

Nicholas Vogelzang, MD: Yes, and you have to do germline testing on these, or can you do it on somatic?

Daniel Petrylak, MD: You can do it on somatic as well as germline.

Nicholas Vogelzang, MD: I believe that PROfound didn’t allow cell-free DNA, or I thought they required somatic, didn’t they?

Daniel Petrylak, MD: They required somatic tissue….

Nicholas Vogelzang, MD: Or was it germline? I can’t remember.

Daniel Petrylak, MD: It was tissue that they used. There’s a difference with other studies where they’re using the liquid biopsy test to look for these particular mutations—TRITON2 and TRITON3—which are using rucaparib rather than using olaparib. TRITON2 is a phase II trial, which has about a 50% response rate in those patients who have BRCA mutations. TRITON3 is a randomized study that would of course confirm the results from TRITON2, but these are a little bit broader in their use of the molecular markers.

Nicholas Vogelzang, MD: I believe we also have a GALAHAD trial.

Daniel Petrylak, MD: GALAHAD trial.

Nicholas Vogelzang, MD: That’s coming, and that’s another PARP inhibitor, right?

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: That has not reported out yet.

Daniel Petrylak, MD: It’s not reported out yet, correct.

Nicholas Vogelzang, MD: We’re going to be dealing in this coming year probably with at least 2, maybe 3 PARP inhibitors.

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: If you’re testing early on in all patients, and if you don’t find a BRCA, or you don’t find a DNA repair deficiency, would you retest your patients?

Daniel Petrylak, MD: I do retest because this could be a clonal evolution of something that may not be picked up in the original test. I’m also excited about drugs that are trying to induce BRCA, and I think that this is going to be the next step in this particular pathway. As we said, only about 20% of patients have this mutation, but then how can we induce the cell to downregulate the DNA repair pathway such that you are sensitive to a PARP inhibitor? And this is where the combination trials are starting to come into play.

Abiraterone downregulates DNA repair enzymes. Hypoxia will do the same thing. At the ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] meeting we saw some other further abstracts looking at the combination of abiraterone plus olaparib. A randomized phase II trial showed an improvement in radiographic progression-free survival. And the interesting thing was it was irrespective of your BRCA. I think that that was a very interesting aside to this particular hypothesis.

Joe Kim, MD, at my institution has looked at olaparib combined with a drug called cediranib, which is also an antiangiogenesis agent. He demonstrated a 7-month improvement in radiographic progression-free survival in favor of the combination. Now we haven’t yet examined the different molecular markers.
 
That analysis is underway. What I thought was particularly intriguing about this case was one of my patients who happens to be a physician, and is BRCA2-positive, he was initially randomized to the olaparib only arm. He had about a 6-month response and then progressed. And the trial allowed for crossover. He went on olaparib/cediranib, he responded again. So this is again a very interesting little observation, and perhaps now we have to start looking at these combinations.

The third combination that I’m excited about is the combination of PARP plus immune checkpoint inhibitors. There is a synergy between the 2, and Fatima Karzai, MD, from the National Cancer Institute a couple of years ago presented some data of a PARP inhibitor combined with a checkpoint, and also saw the same pattern that you did not need to have a DNA repair mutation to have a response. These are ways that we could potentially expand the applicability of these PARP inhibitors to our patients.

Transcript Edited for Clarity
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