February 2020 Edition Vol.11, Issue 2

An Ovarian Cancer Roundtable: The Role of PARP Inhibitors in the Treatment of Ovarian Cancer

Recent findings presented at the 2019 European Society of Medical Oncology (ESMO) annual meeting may herald a paradigm shift with PARP inhibitors in the treatment of advanced ovarian cancer. A panel of experts, led by Brian Slomovitz, MD, Professor and Director of Gynecologic Oncology at the Sylvester Comprehensive Cancer Center at the University of Miami, Miller School of Medicine discussed the expanded role of PARP inhibitors and how these targeted agents are reshaping the treatment landscape of advanced ovarian cancer.

Dr. Slomovitz was joined by Rebecca Arend, MD, Assistant Professor of Gynecologic Oncology at the University of Alabama at Birmingham (UAB) and an Associate Scientist at the UAB Comprehensive Cancer Center Experimental Therapeutics Program, and Thomas Herzog, MD, Deputy Director of the University of Cincinnati Cancer Institute and Professor of Obstetrics and Gynecology at the UC College of Medicine.

The panel discussed the use of PARP inhibitors in the second-line maintenance setting; the role of BRCA testing and homologous repair deficiency (HRD) testing; the role of PARP inhibitors in the first-line setting based on three landmark trials presented at ESMO; and finally, whether PARP inhibitors should be used with bevacizumab in combination or sequentially.

PARP Inhibitor Treatment and Maintenance

There are currently three PARP inhibitors indicated for high-grade epithelial ovarian cancer treatment and maintenance – niraparib, olaparib, and rucaparib.

Dr. Slomovitz: How are you currently using PARP inhibitors in your clinic outside of the FDA indication?

Dr. Arend: I generally will offer PARP inhibitors to anyone at the time of platinum-sensitive recurrence, and I will offer them in all-comers regardless of HR status for maintenance in the platinum-sensitive setting. Then, I use them per indication in anybody who has a BRCA germline or somatic mutation. Recently, I have started to use niraparib as indicated as a maintenance therapy for HRD-positive [advanced disease], and based on data from the SOLO-1 trial, I use olaparib as frontline maintenance for patients with somatic and germline mutations.1

Dr. Slomovitz: I think all of our patients with ovarian cancer really deserve a PARP at some point in their treatment regimen… the one indication for all of our patients is in the second-line maintenance setting, and we know that there are three PARPs that are FDA approved for this indication: niraparib, olaparib, and rucaparib.

Dr. Herzog: There were three Phase 3 trials for each of those PARPs you just named: SOLO-2 with olaparib2, the NOVA trial being with niraparib3, and ARIEL3 with rucaparib4… All three [PARPs] are indicated for patients who have platinum-sensitive disease, meaning the disease is at least six months out from the time of prior platinum, before there’s evidence of recurrence. If those patients respond to the new platinum-based regimen, with at least four cycles of platinum, then they’re then eligible to receive a PARP.

All of these trials were up against placebo, but they shared a very impressive advantage in terms of progression-free survival. You have to be careful about comparing across trials, but, while there were definite differences among these studies, the control arms were very similar, and they all had amazing hazard ratios, between 0.2 and 0.3, among patients with a BRCA mutation. All of these PARPs had approximately the same efficacy. What’s really interesting is how much we’ve grown the pie in terms of who benefits from them.

For me, the selection is based on insurance coverage and prior toxicity because there are differences in toxicity profile. There are also idiosyncratic differences, such as dosing, that could influence compliance. All of these factors help determine which particular PARP I’m going to recommend in the platinum-sensitive maintenance setting.

Dr. Slomovitz: It doesn’t matter which one; it’s the class that’s demonstrating the efficacy, especially in the second-line maintenance setting… For gynecologic oncology, this is the first time we’ve had three drugs in the same class we can choose from… If a patient is not doing well with one of the side effects, such as platelets, for example, I’ll switch to niraparib. On the other hand, if a patient is experiencing gastrointestinal side effects, and I want to prescribe one pill per day, I would switch from olaparib or rucaparib to niraparib.

BRCA/HRD Testing

As Dr. Slomovitz noted, data from the NOVA trial showed that all-comers are eligible for PARP inhibitors in the platinum-sensitive setting as progression-free survival was improved in patients with or without BRCA mutation.

Dr. Slomovitz: How are you incorporating BRCA testing and HRD testing into your practice now? Are you doing it immediately at diagnosis or later, knowing that a PARP inhibitor is in the patient’s future?

Dr. Herzog: As someone who has to face patients, I was excited by the fact that I had another option for those who did not have a mutation and/or any other evidence of homologous repair problems. I was not doing a lot of testing after the platinum-sensitive studies came out, but ARIEL3 showed a big benefit among patients with homologous recombination deficiency… Testing continues to evolve, and since the ESMO data, I’m now using it more in the frontline setting. We’ve been doing most of our HRD testing through Myriad.

Dr. Arend: We now do germline testing in addition to full-panel next-generation sequencing on all of our ovarian cancer patients. I use FoundationOne with LOH (loss of heterozygosity) status, which gives me the full spectrum of other mutations for future clinical trials like the TAPUR trial and other biomarker studies.

Dr. Slomovitz: I think everyone with ovarian cancer deserves a BRCA test, at least for the benefit of other relatives. Patients are all going to get PARP inhibitors, but a BRCA test [could be used] to prevent other cancers for themselves or for other family members. HRD testing or next-generation sequencing used to be a problem when they were cost prohibitive, but the MATCH trial and other clinical trials are looking at certain mutations, so sequencing the full tumor has become beneficial and is probably worthwhile at some point along the treatment course. Patients can even order the hereditary test online at home… as long as the patients are educated about the results.

What is more important, HRD or BRCA?

In women with newly diagnosed stage III/IV ovarian cancer, PRIMA/ENGOT-OV26/GOG-3012, PAOLA-1/ENGOT-ov25, and VELIA/GOG-3005 evaluated three PARP inhibitors: niraparib (as maintenance), olaparib plus bevacizumab (as maintenance), and veliparib (with chemotherapy, then maintenance). These three landmark trials were presented at the 2019 ESMO annual meeting.

Dr. Arend: These trials all evaluated PARP inhibitors for up-front maintenance, and all three trials included all-comers, regardless of HRD status. Both the PRIMA trial5 and PAOLA-1 trial6 had two arms, whereas the VELIA trial7 had three arms. PRIMA did not allow bevacizumab, but in PAOLA-1, the experimental arm and the control arm included bevacizumab. PRIMA evaluated just maintenance with niraparib. PAOLA-1 had carboplatin/paclitaxel plus or minus olaparib for the maintenance portion. VELIA tested veliparib earlier in the disease continuum—with carboplatin/paclitaxel—plus or minus veliparib for maintenance.

In all of these PARP inhibitors, we were able to see efficacy in all-comers. Similar to what’s seen in the maintenance setting in platinum-sensitive disease, however, patients with BRCA mutations did better. With HR deficiency compared to HR proficiency, we saw similar results to the maintenance setting, but the difference is that we don’t know yet whether the patients are platinum-sensitive in these up-front trials. It’ll be extremely interesting to see what happens with the biomarkers when the FDA evaluates the data… Biomarker testing may potentially play more of a role in the up-front setting, but if you do look at the hazard ratios in the all-comers and you compare them to those leading to the FDA approval of bevacizumab, they’re not all that different to me.

Dr. Herzog: There’s a natural tendency to want to do cross-trial comparisons, but there’s some really unique differences among all these trials. The bottom line is: they all hit their primary endpoint, which is really impressive, with hazard ratios below 0.45. When have we ever seen that compared to chemotherapy? I think these data are transformative, and I think they’re going to change practice.

Dr. Slomovitz: When you looked at the bevacizumab and olaparib in the HR-deficient or in the HR-proficient group, there really wasn’t much of a difference between the two. Maybe it’s because we’re getting the maximum benefit out of bevacizumab or maybe the olaparib could have done that by itself, but we’ll see. In the VELIA trial, veliparib was active, but do we need to give this drug during chemotherapy? I’m not sure about that yet. I think the key to maintenance therapy is to expose patients to a drug over a period of time. Carboplatin and paclitaxel are effective agents. Veliparib during chemotherapy may be adding toxicity without much benefit, and I’m not sure if it’s needed there.

Dr. Arend: PAOLA-1 raises another question: do we need the bevacizumab, especially in BRCA-positive patients and maybe even in HR deficient patients? It’ll be interesting to see how it all pans out.

Sequencing of PARP Inhibitors

Dr. Slomovitz: Assuming maintenance therapy options are bevacizumab and PARP inhibitor in the first- and second-line setting, do you combine them as maintenance in the first-line setting based on PAOLA-1? Do you hold off on one? Which do you choose first?

Dr. Herzog: You can’t deny that the PAOLA-1 trial had really impressive data, but it also had fairly increased toxicity. I think tolerance profiles and financial considerations are going to factor in on this to some degree as well, although biosimilar use in competition among the PARPs will likely lower the cost of that combination as we move forward. For me, I think that it’s about making decisions, and those decision points [begin] when you first encounter a patient with frontline ovarian cancer: When are you going to do the surgery? Are you going to do neoadjuvant chemotherapy or not? Are you going to do primary cytoreduction?

Then you need to think about when to start an additional agent such as bevacizumab. I personally don’t use bevacizumab in everyone, only in those who have high-risk disease characteristics. For example, I use bevacizumab in patients who have pleural effusions and high-volume ascites because I think it does such a great job drying those effusions up. If I have a patient on bevacizumab, and she’s doing really well, I’m going to be reluctant to take her off, so it’s nice to have the ability to then add a PARP after considering HRD and BRCA status. If I don’t have those tests, the PRIMA data are very clean.

The VELIA data are going to take some more digesting because we’re not supposed to look at the subgroup analysis just yet. For me, PRIMA and PAOLA-1 data have more immediate clinical use in the frontline setting, which will then affect second decisions.

Dr. Arend: When first encountering the patient, clinicians must decide whether to do neoadjuvant chemotherapy or primary debulking surgery. In the high-risk category, where we know outcomes are likely going to be suboptimal, I think most of us will go the neoadjuvant route. I traditionally do not use bevacizumab in the up-front setting. I will add it after neoadjuvant chemotherapy in high-volume disease if there’s a lot of residual disease or a lot of ascites. If you’re not a bevacizumab user from the very beginning, I think it’s tough. I think that’s what’s difficult with the VELIA study: Why am I being forced to make that decision from the get-go? I think it’s an evolving paradigm. The second point of decision making is whether to add maintenance or not. For me, if somebody has horrible ascites and a great response to bevacizumab and she happens to be BRCA-mutated, I might be reluctant to stop bevacizumab, especially if she still has some residual disease. I like the idea of having the option to add a PARP on top of it if I want to.

In terms of biomarkers, it’s going to be really interesting to see how it all pans out. In an ideal world, all three [PARPs] would be approved in all-comers. That does not mean I’m going to use them in everyone all the time, but that gives us the choice.

Dr. Slomovitz: In the VELIA trial, there was an early signal that giving a PARP inhibitor with chemotherapy may convert some of the progressors to responders, but further analysis is definitely needed.

Summary Points

Dr. Slomovitz: The nice thing about the data that came out at ESMO is that it confirmed the SOLO-1 data. There actually may be a group of BRCA-positive ovarian cancer patients who can remain free of disease progression if they get a PARP inhibitor from the first line. That we can actually say that to a subgroup of women with ovarian cancer is impressive.

Dr. Arend: If you look at how much the use of PARPs is exploding in other tumor types, the fact that it was done first in ovarian cancer means a lot. This is an exciting time for ovarian cancer treatment and developmental therapeutics. We’re starting to understand that not every ovarian cancer is the same and we’re individualizing patients accordingly. From the beginning to the end of treatment, it’s no longer going to be just carboplatin/paclitaxel followed by platinum and then bevacizumab. We’re going to have a lot more options, which I think is exciting.

Dr. Herzog: The bad news is that treating ovarian cancer patients, even in the frontline setting, has become much more complicated. Now, you’re going to have to have a lot more knowledge of what you’re doing to personalize this for the best advantage of the patient. The good news is that good clinicians like options, and we have been provided options. These data are practice changing. We will now be able to incorporate PARP inhibition with or without chemotherapy, and with or without bevacizumab in maintenance, which is really going to be exciting. The future is going to be about personalized medicine and combination therapies – how we combine antiangiogenics and our PARP inhibition platform with immune checkpoint inhibitors and other immunotherapies as well as other novel platforms that are very promising. Treatment has gotten a lot more complicated, but hopefully we’re going to have results to justify that complication.

 


References

  1. Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2018 Dec 27;379(26):2495-2505. DOI: 10.1056/NEJMoa1810858.
  2. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1274-1284. DOI: 10.1016/S1470-2045(17)30469-2.
  3. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016 Dec 1;375(22):2154-2164. DOI: 10.1056/NEJMoa1611310.
  4. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Oct 28;390(10106):1949-1961. DOI: 10.1016/S0140-6736(17)32440-6.
  5. González-Martin A, Pothuri B, Vergote I, et al: Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019 Dec 19;381(25):2391-2402. DOI: 10.1056/NEJMoa1910962.
  6. Ray-Coquard I, Pautier P, Pignata S, et al: Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med. 2019 Dec 19;381(25):2416-2428. DOI: 10.1056/NEJMoa1911361.
  7. Coleman RL, Fleming GF, Brady MF, et al: Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019 Dec 19;381(25):2403-2415. DOI: 10.1056/NEJMoa1909707.

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