PARP Inhibitors: Deciding Among the Available Agents
Angeles Alvarez Secord, MD, reviews the available poly (ADP-ribose) polymerase (PARP) inhibitors and their approved indications and explains why she recommended rucaparib to her patient, Michelle Berke.
PUBLISHED December 27, 2017
Angeles Alvarez Secord, MD: Michelle, we were talking about some of the exciting new drugs that are available in ovarian cancer, and you’re on a PARP inhibitor. I want to share some of the decisions that we went through in terms of deciding when to use a PARP inhibitor for you, and which one. I want to go back to when you finished your second-line treatment of chemotherapy. You were on bevacizumab, and we did maintenance bevacizumab. That was actually a while ago. I don’t know if you realized this at the time, but none of the PARP inhibitors had been approved for maintenance yet. So, it wasn’t even an option that came up for us at that time.
Michelle Berke: Yes, I remember that. I think it came out in December of 2016?
Angeles Alvarez Secord, MD: Now, it is an option. If we were to go back in time, would our decisions be different?
Michelle Berke: That’s a good question.
Angeles Alvarez Secord, MD: It’s always hard to know.
Michelle Berke: Yes. I’m just glad that it came out when it did.
Angeles Alvarez Secord, MD: Right. Right now, there are 2 PARP inhibitors that are approved in the maintenance situation. Those are olaparib and niraparib. And the approval for those PARP inhibitors, in that maintenance situation, when a patient had platinum-sensitive chemotherapy and they responded to their chemotherapy with either a complete response or a partial response, is for all-comers. So, you don’t have to have a mutation.
Michelle Berke: That is interesting.
Angeles Alvarez Secord, MD: You have a BRCA1 germline mutation, right? In this situation, any patient who is platinum sensitive, who responds to that chemotherapy, can go on a PARP inhibitor for maintenance treatment. And for somebody who has had a BRCA1 or BRCA2 mutation, with either a germline mutation, like you do, or a mutation that is just in a tumor, the benefits, in terms of disease control, are pretty outstanding. We’re talking not just twice as long, but almost 3 or 4 times as long.
Michelle Berke: Really?
Angeles Alvarez Secord, MD: Yes, it’s pretty dramatic. I’d give you the numbers. It doesn’t even really pop out, in terms of the improvement on the curves. We’re talking 19 versus 5 months, or 16 versus 5 months.
Michelle Berke: That’s a huge difference.
Angeles Alvarez Secord, MD: There’s some differences in terms of how you assess that data. But the bottom line is, it works, right? If somebody doesn’t have one of those mutations, but let’s say they have another mutation that’s associated with homologous recombination defects, there’s still a benefit. It’s not quite as strong, but I think it was a 6- to 9-month benefit in those situations. And again, you have to take these numbers with a grain of salt. The bottom line, though, is that it does work in that situation. And then, if somebody doesn’t have the mutation at all, the benefit is less. It’s about a 3-month range of disease control. You have to be careful with the numbers because of other things, such as the hazard ratio. You’re basically decreasing the risk of disease from coming back by in some cases 40%, if somebody doesn’t have the mutation or the homologous recombination defect. I gave you a lot of information.
Michelle Berke: Yes.
Angeles Alvarez Secord, MD: But as a patient, what do you think of when somebody tells you all of that information?
Michelle Berke: As a patient you go by statistics, a lot, because you want the best treatment that you can possibly get. So, if statistics are looking good, in my favor, then that’s my decision. That’s what I base my decisions on.
Angeles Alvarez Secord, MD: And with the BRCA1 mutation, it would look really good to get one of these drugs. They weren’t available for you at the time. We did bevacizumab, which I think makes a lot of sense given the data. You progressed. At that point, we did talk about the fact that there was a drug available called rucaparib. That’s a different PARP inhibitor. Rucaparib is one of the PARP inhibitors that’s now been approved for treatment, right?
Michelle Berke: OK.
Angeles Alvarez Secord, MD: The other PARP inhibitor that’s approved for treatment is olaparib. I just want to go over this again because it’s very confusing.
Michelle Berke: It is very confusing.
Angeles Alvarez Secord, MD: There’s 3 PARP inhibitors. They have different indications from the US Food and Drug Administration regarding when you can use them and in which patients you can use them. The maintenance indications are for niraparib and olaparib, and the treatment indications are for olaparib for patients who have a germline mutation, only.
Michelle Berke: Like me?
Angeles Alvarez Secord, MD: Yes, like you. And, these patients have had at least 3 prior chemotherapies. And then, the other one is rucaparib. Rucaparib is for patients who either have a germline mutation or somatic mutation. That means a mutation that is just in the tumor. They didn’t inherit it from a parent. They have a de novo mutation in the tumor, and have had 2 prior chemotherapies. You can actually use rucaparib sooner than you can use olaparib. I think at some point, these distinctions are going to be a wash and all of these PARP inhibitors are going to be approved across the board.
Michelle Berke: Good.
Angeles Alvarez Secord, MD: But right now, how we make those decisions is really based on the indication, the tumor, and the genetic germline mutation biomarker. So, it’s really important that patients have the conversation with their physician about which of these PARP inhibitors, if any, may be appropriate for them. That’s one part of the treatment decision, right? Then, the other part is a side effect profile. In your situation, we had rucaparib as an option. We went for it.
Michelle Berke: It actually became available right when I needed it.
Angeles Alvarez Secord, MD: It was perfect timing.
Michelle Berke: It was very perfect timing.
Angeles Alvarez Secord, MD: What has your experience been with rucaparib, so far?
Michelle Berke: The side effects have been minimal. I have drainage in my eyes and my nose, and abdominal cramping once in a while. Fatigue is still there, but that’s pretty much it. I’m doing really well on it. Sometimes, I get nauseous and I can’t eat.
Angeles Alvarez Secord, MD: How do you feel on the drugs, as compared to everything you’ve gotten throughout this whole experience?
Michelle Berke: It’s the best I’ve felt in over 4 years. My quality of life is really good right now.
Angeles Alvarez Secord, MD: That really strikes me. It’s the best you have felt in 4 years. That includes the time that you came off of any treatment and you were in your first remission. This is the best you have felt.
Michelle Berke: Yes, this is the best, even compared to when I was in remission for 6 months. That’s how well this drug is working for me.
Angeles Alvarez Secord, MD: Right. I think that for some patients, these drugs could potentially represent a cure for someone with platinum-resistant or platinum-sensitive recurrent ovarian cancer. They’ve had some patients on these drugs, long-term. And one of the studies, Study 19, which is an olaparib study, now reveals data going out 5 years. There’s a few patients that are long-term survivors.
Michelle Berke: That’s really good news.
Angeles Alvarez Secord, MD: Michelle, going to back to when we talked about starting on a PARP inhibitor, we knew that option was potentially coming months before it was even available. I know that your daughter even knew it was coming?
Michelle Berke: Yes. She works for a clinical trial company.
Angeles Alvarez Secord, MD: She’s very smart and she was very interested in PARP inhibitors for you. But not everybody knows about these drugs, right? Maybe some of our patients don’t know about them. Maybe some of their doctors don’t know about them either. I personally think the PARP inhibitors and their approval in ovarian cancer is the most exciting thing we’ve had happen in years.
Michelle Berke: I agree.
Angeles Alvarez Secord, MD: It’s transformative. So, I would like to shout out to all patients that they should have PARP inhibitors on their radar. Ask your doctor about them. See if you’re a candidate for these drugs. And then, when you’re making decisions about which drugs to use, discuss the side effect profiles, how many pills you have to take, and, obviously, the cost. Would you add anything to that?