Advent of PARP Inhibitors in Metastatic CRPC

EP: 1.Overview of Metastatic HSPC: Diagnosis and Risk Stratification

EP: 2.Systemic Treatment Armamentarium in Metastatic HSPC

EP: 3.What is the Role of Locoregional Therapy in Metastatic HSPC?

EP: 4.Informing Systemic Therapy Selection With Negative Data in HSPC

EP: 5.Evolving Treatment Landscape of Nonmetastatic Castration-Resistant Prostate Cancer

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EP: 6.Advent of PARP Inhibitors in Metastatic CRPC

EP: 7.Combination PARPi Strategies in Metastatic CRPC: Interpreting Data From Clinical Trials

EP: 8.Radioligands in the Treatment of Metastatic CRPC: Lutetium-177–PSMA-617

EP: 9.Radioligands in the Treatment of Metastatic CRPC: Radium-223

EP: 10.Metastatic CRPC: Novel Treatment Strategies With Radioligand Therapy

EP: 11.Novel Therapeutic Targets in Metastatic CRPC

EP: 12.Potential for CDK4/6 Inhibitors in Metastatic CRPC

EP: 13.Ongoing Clinical Trials in the Metastatic CRPC Setting

EP: 14.CAR T-Cell Therapy in Metastatic CRPC and Future Directions in Care

Transcript:

Rana McKay, MD:This is a great segue into the metastatic CRPC [castration-resistant prostate cancer] landscape. Maybe we dive right in first with PARP inhibition [and] genetic profiling. First, we’ll start with who do you test? When do you test? How do you do it?

Ulka Vaishampayan, MD:Hopefully, you have tested the patient pretty much at metastatic disease because that’s NCCN [National Comprehensive Cancer Network] guidelines allow you to test them for metastatic disease or high-risk localized disease also. You can test at an earlier stage, even if you’re going to only consider treatment at the castrate-resistant phase. Usually, most patients should be tested by the time they turn castrate resistant but if they’re not, absolutely I would recommend testing at that point when they have metastatic-castrate resistance disease. Then the consideration of the therapy, the other controversy now is whether you use it in everybody—it’s not FDA-approved right now for that—or do you only focus on the HRR [homologous recombination repair]-mutation patients. And that so far all we’ve seen is progression-free survival benefit, which in all-comers in combination with one of the androgen receptor inhibitors or abiraterone [Zytiga]. I don’t know if we have enough as of now to use it in everyone. Definitely for the HRR mutation patients it should be considered as a treatment option but not yet in everyone.

Sumit K. Subudhi, MD, PhD:And that’s for the BRCA.

Rana McKay, MD:Regarding the testing, do you guys test the primary? Do you repeat the biopsy? Do you get a blood test? What’s your approach in the clinic?

Sumit K. Subudhi, MD, PhD:I like Ulka’s approach of at the time of knowing the patient has a high-risk disease, whether it’s a primary or metastatic side, I try to send that out for somatic testing. I also like to do germline testing at the same time. And then at the time of progression, I also like to re-biopsy. And the reason why is sometimes you’ll see new mutations that you didn’t see earlier on. New somatic mutations.

Rana McKay, MD:Do you integrate cell-free DNA at that time point?

Sumit K. Subudhi, MD, PhD:I do, actually. I do wait for the patient to have metastatic disease because what we find is that the lower the disease burden, the less likely the cell-free DNA will be informative.

Rana McKay, MD:First, let’s dive into the monotherapy data. We’ve got 2 drugs. We’ve got rucaparib [Rubraca]. We’ve got olaparib [Lynparza]. Maybe we’ll start with the olaparib data. Where’s the indication there? How do you all use that in the clinic? Just as a monotherapy.

Arash Rezazadeh Kalebasty, MD:Well, I use it when you have the BRCA-mutated patients, not really in all PARP biomarkers. They’re the ones that we have tried like ATM, and it really doesn’t work. You call it the PARP biomarker, but when you look at data [we have] yet to see patients who have done well with it. I select the patients who have the PARP biomarkers based on the individual mutation, rather than give it to all-comers. I have seen it in the clinic, which can be seriously difficult to tolerate in some patients. We get a lot of GI [gastrointestinal] symptoms. So it’d be justifiable if you want to give it if there’s enough efficacy for you to tolerate the side effects.

Rana McKay, MD:Then when you were thinking about the biomarker positive, I know there’s a lot of heterogeneity within that biomarker positive group. What do you think about that in the clinic? Is it only BRCA1/2, PALB2, ATM, CHEK2, CDK12. How do you think about that?

Arash Rezazadeh Kalebasty, MD:Go ahead, if you want, please.

Sumit K. Subudhi, MD, PhD:I usually give it to patients with BRCA1 or BRCA2 mutations. We have a phase 1 clinic that has a next-generation PARP inhibitors. Then the patients with the other mutations can go in and try those out. Just because, as you said, especially the ATM mutations do not do well with the monotherapies with the first-generation PARPs.

Rana McKay, MD:And what about rucaparib? Are you all using rucaparib?

Ulka Vaishampayan, MD:Post chemotherapy. That’s an indication for rucaparib. I use it. And now if you’ve used chemotherapy in the hormone-sensitive phase, then frequently people come into mCRPC with being pretreated with ARSI [androgen receptor signaling inhibitor] and chemotherapy. Really, you could use either one of the PARP inhibitors.

Rana McKay, MD:I think the data from the TRITON3 study [NCT02975934] were so intriguing in the control arm of that study. They had abiraterone, enzalutamide [Xtandi], or docetaxel physician’s choice. And it’s the first data that we’ve seen where we’re actually looking at, potentially the role of what’s the study sequence of a PARP inhibitor? Do you do it pre-chemo? Do you do post-chemo? Is it better to do it pre or post? How do you all integrate that data into your practice?

Ulka Vaishampayan, MD:I think it’s impressive to see a superiority to docetaxel, which no other agent has shown so far. That is an intriguing part of that TRITON study. I think it strengthens my reason to use rucaparib.

Scott Tagawa, MD, MS, FACP:It strengthens my data and my personal practice to use a PARP inhibitor prior to chemotherapy in selected patients, specifically BRCA2. I’m not sure about BRCA1 but BRCA2 for sure. Probably BRCA1, and that’s what I was doing with olaparib. So would I ever treat someone with an ATM [mutation]? Yeah. [They] had everything else, doesn’t qualify for a clinical trial. I’m probably going to try a PARP inhibitor with some of those other alterations. I agree those are probably not the best ones. The nice thing is not just the efficacy data, but also the AE [adverse event] data. It’s a pill. It’s a targeted pill. But it’s not without AEs and the AEs were not necessarily worse, I’ll not say better than docetaxel. It depends on what we’re looking at. And I think it’s important and I tell patients all the time because we’ve seen that. Let’s say they didn’t want chemotherapy. I’ll say “OK. It’s intravenous but it may not be easier than a pill.”

Rana McKay, MD:Very good point. I think PARP inhibitors are certainly here to stay for people with advanced prostate cancers, certainly right now, and the selected population. I think a lot of controversy around which mutation and what’s the effect size of benefit for anybody with any one given mutation.

Arash Rezazadeh Kalebasty, MD:I want to add a point to discuss chemotherapy. I have had patients who actually prefer chemotherapy, the ones who got PARP inhibitor afterward, to say at least I had 1 bad week and 2 good weeks with chemotherapy, but this is every day. And so, the toxicity is continuous versus chemotherapy is up and down, so they get a break.

Ulka Vaishampayan, MD:The other point I would make is based on today’s tele pro presentation for BRCA2 patients. Does it actually sensitize the second ARSI to a response with the addition of PARP inhibitors? I don’t know because we didn’t do a single agent PARP study there.

Scott Tagawa, MD, MS, FACP:Agreed.

Ulka Vaishampayan, MD:You just did a secondary ARSI plus/minus PARP, and we are not quite able to separate that out, but it was just intriguing that they actually had a subset of the population who had received prior abiraterone and they seem to show a benefit with enzalutamide plus PARP.

Transcript edited for clarity.