Ovarian Cancer: Talking to Patients About PARP Inhibitors
Insights From: Angeles Alvarez Secord, MD, Duke University Medical Center; Michelle Berke
Angeles Alvarez Secord, MD: Michelle, thank you for being here with me today.
Michelle Berke: Thanks for having me.
Angeles Alvarez Secord, MD: We’re going to discuss PARP inhibitors and how they have transformed ovarian cancer care. And you’re a great person to talk to because you’ve been on a PARP inhibitor, rucaparib, for treatment of ovarian cancer.
Michelle Berke: I’ve been on it since mid-June.
Angeles Alvarez Secord, MD: Which is a perfect opportunity to share your experience with all of the oncologists who are considering treating their patients with PARP inhibitors.
Michelle Berke: Oh, PARP inhibitors are a dream come true for me. My first frontline therapy was carboplatin with paclitaxel and Avastin (bevacizumab). I had a lot of really bad side effects from that first frontline therapy. With PARP inhibitors, I have very few side effects.
Angeles Alvarez Secord, MD: Right. So, I believe that PARP inhibitors and their FDA approval and inclusion in the treatment of ovarian cancer has certainly been transformative, and where we are in the treatment landscape of ovarian cancer. Before PARP inhibitors, we have had biologic therapy, such as bevacizumab. But for the most part, it was really chemotherapy, and while these drugs do have side effects, they don’t tend to be as severe as some of the chemotherapy side effects that we see. So, I think it’s an invaluable opportunity for you to share the stage with me and share your experience.
Michelle Berke: Yes, I’m doing great on this. The side effects for me, I have a little nausea once in a while, abdominal cramping once in a blue moon, some nasal drip, but other than that, it’s just fatigue. I’m doing great on this.
Angeles Alvarez Secord, MD: So, currently, there are 3 PARP inhibitors that have been FDA approved. Two of them for the treatment of recurrent ovarian cancer, and then two for maintenance therapy in women with platinum-sensitive ovarian cancer who respond to retreatment with platinum-based chemotherapy. So, I’m just going to go through those a little bit. The 2 that have been approved for the treatment of recurrent ovarian cancer are olaparib, and that is approved for women who have either a germline BRCA1 or BRCA2 mutation and have had 3 prior lines of therapy.
Michelle Berke: OK.
Angeles Alvarez Secord, MD: And then there’s rucaparib, which is a PARP inhibitor that is approved for women with recurrent ovarian cancer who have had 2 prior chemotherapies and have either the germline mutation or a somatic mutation. That means the mutation is just in the tumor, but they didn’t inherit it from a parent. And then we have the maintenance situation, which is a little different because the PARP inhibitors that are approved there are olaparib and niraparib, and I think soon we’ll see an approval for rucaparib in that space as well.
Michelle Berke: Oh, interesting, OK.
Angeles Alvarez Secord, MD: Just based on a new study that was released called ARIEL 3, that was recently published showing that similar to the other PARP inhibitors, rucaparib also prolonged disease control in women who had platinum-sensitive cancer who had either a complete response or partial response to platinum-based therapy. So, it does get confusing. But in that space, it’s all comers. So, women don’t have to have the mutation in BRCA1 or BRCA2 to be able to get this drug.
Michelle Berke: Oh, interesting. I didn’t know that, OK.
Angeles Alvarez Secord, MD: Right, it’s very interesting. And so, one of the first drugs that was evaluated was niraparib on the NOVA trial. So, women who had platinum-sensitive ovarian cancer who had a complete response or partial response to therapy could go on a study, and then there were 2 groups. There was 1 group that had the germline mutation, and then the other group did not have the germline mutation, or the nongermline cohort. So, they’re called cohorts, right? And they found that in the entire group overall, there was a benefit to PARP Inhibitor therapy in terms of prolonging disease control. And that the greatest benefit was actually seen in the women who had a germline mutation in BRCA1 or BRCA2, and that benefit was 21 months versus 5 months which is… I see your face.
Michelle Berke: Wow, 21 or 5.
Angeles Alvarez Secord, MD: Yes, no brainer there.
Michelle Berke: It’s a no brainer, yes, I’ll take the 21.
Angeles Alvarez Secord, MD: And so, what was surprising, too, is people had this idea, “Oh, these patients, they’re all platinum-sensitive, they’re going to be so great on chemotherapy anyway.” But 5 months doesn’t seem like that’s so great on chemotherapy, right? And also, you have a BRCA1 mutation. When you got retreated with platinum-based therapy, you didn’t have a complete response. You had a good response, it was a partial response.
Michelle Berke: But not complete. Not what we were hoping.
Angeles Alvarez Secord, MD: So, I think sometimes the reality isn’t always what we remember.
Michelle Berke: I agree.
Angeles Alvarez Secord, MD: So, going back to this study, when they further divvied up these groups, they saw a benefit in the nongermline cohort as well. But it wasn’t quite as strong, but it was still significant reduction in risk of the progression, meaning better disease control. I think it was about 60% better disease control in that group.
Michelle Berke: Wow, OK.
Angeles Alvarez Secord, MD: And then they further broke that down. Stay with me because this is confusing.
Michelle Berke: It’s very confusing, but I’m here.
Angeles Alvarez Secord, MD: In the patients who had a tumor that had positive HRD, which is homologous recombination defects, and that was based on a special test they do, it’s a myriad test and it uses a certain score, if they scored greater than 42, they were said to have the HRD-positive. And so, in that group again they showed this benefit, as well as patients who had the tumor BRCA mutations that weren’t inherited. And they even showed a benefit in the patients who were completely biomarker negative. They didn’t have a germline mutation, didn’t have HRD, and they demonstrated a disease control benefit of about 3 months, which isn’t as… your face is so different.
Michelle Berke: I know, but you know 3 months. That’s better than nothing.
Angeles Alvarez Secord, MD: Right. But when I said that first one with the BRCA, I saw you light up then. So, the negative is not quite as strong.
Michelle Berke: It’s not.
Angeles Alvarez Secord, MD: That’s what’s sometimes difficult in terms of making a decision because you were on bevacizumab, which also has about a 3-month disease control rate. So, trying to decide between those 2 in that biomarker population can be challenging. So, that was the niraparib trial. Because they saw that benefit in all-comers, the FDA approved it for all patients. You don’t have to have a test.
Michelle Berke: Mutation.
Angeles Alvarez Secord, MD: Right. You don’t have to have a mutation, you don’t have to have a defect. You don’t need to have a test to show that there’s a mutation or HRD-positive tumor to be able to give the patient the drug. So, that was that test. Now the olaparib study, there were 2. Study 19 was the first study that showed benefit of these maintenance treatments. In that study, it was all comers but it was a small phase II trial. And again, with olaparib, they showed improved disease control and the entire group was using the maintenance PARP inhibitor. And again, it was in patients who had platinum-sensitive disease who had either complete response or partial response to platinum therapy.
What’s interesting is that study probably wasn’t large enough to get the support it needed to move, and to get FDA approval. So, they followed it up with another study and the study design was only for women who had a germline BRCA1 or BRCA2 mutation. And that’s because in that group, they found this ridiculous improvement in progression-free survival. It was amazing. They were able to control the disease, reducing the risk of disease progression by 80%.
Michelle Berke: Wow. That’s really good news.
Angeles Alvarez Secord, MD: Right. So, then the SOLO-2 trial, they limited it to the population where they saw the biggest benefit. And, again, they saw this whopping improvement in progression-free survival. That was approved by the FDA not just for that select group that they studied, but for all comers, based in part, I think, on the Study 19, the smaller study, but also probably from the NOVA information as well. So, that’s how we have those 2 studies there.