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Three pivotal clinical trials evaluating PARP inhibitors have significantly impacted the treatment of patients with newly diagnosed ovarian cancer.
Angeles Alvarez Secord, MD
Three pivotal clinical trials evaluating PARP inhibitors have significantly impacted the treatment of patients with newly diagnosed ovarian cancer, according to Angeles Alvarez Secord, MD, and with these agents approved for use as frontline maintenance in this disease, the role of biomarkers has become an important topic of discussion.
Based on data from the pivotal phase III PRIMA trial, frontline treatment with niraparib (Zejula) represents a new standard of care in patients with newly diagnosed, platinum-sensitive advanced ovarian cancer. Niraparib improved median progression-free survival (PFS) by 5.6 months compared with placebo in this patient population. In the overall population of those enrolled on the trial, the median PFS was 13.8 months with niraparib versus 8.2 months with placebo, translating to a 38% reduction in the risk of progression or death (HR, 0.62; 95% CI, 0.50-0.76; P <.001).1
Frontline veliparib was evaluated in combination with carboplatin and paclitaxel followed by veliparib maintenance in patients with high-grade serous ovarian cancer in the phase III VELIA trial. Among the study population, the median PFS was 23.5 months versus 17.3 months in the veliparib arm and the placebo arm, respectively (HR, 0.68; 95% CI, 0.56-0.83; P <.001). In those with BRCA1/2 mutations, the median PFS was 34.6 months with veliparib versus 22.0 months with placebo (HR, 0.44; 95% CI, 0.28-0.68; P <.001).2
Lastly, in the phase III PAOLA-1 trial, the combination of olaparib (Lynparza) and bevacizumab (Avastin) were evaluated in the frontline setting. Results showed an improvement in median PFS by 5.5 months with olaparib/bevacizumab compared with bevacizumab/placebo in patients with newly diagnosed, advanced disease following prior treatment with platinum-based chemotherapy plus bevacizumab. Median PFS was 22.1 months in the olaparib arm versus 16.6 months in the placebo arm (HR, 0.59; 95% CI, 0.49-0.72; P <.0001).3
It is important to consider the different patient populations evaluated in each trial and the benefit of the agents in these subgroups, according to Secord.
“The main message is that there is not necessarily one right answer [when it comes to choosing among the PARP inhibitors],” said Secord, a gynecologic oncologist at Duke Cancer Center. “It’s a little bit more complex than that; it’s important to consider shared decision making.”
In an interview with OncLive during the 2020 SGO Winter Meeting, Secord discussed how PARP inhibitors are being used in ovarian cancer, the data to consider when choosing among the agents available in practice, and the financial toxicities associated with this treatment.
OncLive: What is the current role of PARP inhibitors in ovarian cancer?
Secord: The role of these agents is actually quite expansive. We have indications for using PARP inhibitors in women in the frontline setting who have a BRCA1/2 mutation in their tumors that are either germline or somatic. We also have indications in the treatment setting for rucaparib (Rubraca) and olaparib for patients with BRCA1/2 mutations, as well as an indication for niraparib in women with platinum-sensitive tumors that have homologous recombination deficiency (HRD). All of those drugs in the platinum-sensitive setting are indicated for all-comers, regardless of their biomarker status.
Could you discuss the pivotal trials examining PARP inhibitors in ovarian cancer?
I did a symposium in conjunction with Jubilee Brown, MD, of Levine Cancer Institute, Atrium Health, and she was a great partner in putting this together. The focus of the symposium was digesting [the data from the] PAOLA-1, PRIMA, and VELIA trials. We wanted to focus on discussing the real-world implications of these data with our audience. We considered how others are applying this information to practice and any issues they are finding that might prevent the use of these medications in the frontline treatment of women who are candidates for these agents. We are focusing on women with newly diagnosed ovarian, fallopian tube, and peritoneal cancer. It was a very engaging experience working with the other physicians and advanced healthcare care providers in the field.
What are the real-world implications of these data?
We submitted [requests] to the SGO members [to share the] interesting cases they have had. We chose 2 cases from all the responses we received. We highlighted 2 different situations in women with newly diagnosed ovarian cancer. In 1 situation, the patient had a BRCA1/2 somatic mutation, and in the other, the patient had a [BRCA1/2] germline mutation.
We focused on these patients and discussed the disease characteristics that they had, their biomarker status, and how we would treat them. In each of these cases, the women had a BRCA1/2 tumor mutation, so they were candidates for olaparib, which is an FDA approved agent.
We also tried to delve into these different areas in terms of the trials. We changed things up and said, “What would you do if your patient didn’t have these mutations, but they had an HRD tumor?” We essentially explored the role of niraparib per the PRIMA protocol. Another scenario we evaluated was, “If the patient had been started on bevacizumab, what would you do in the maintenance setting? Do you add olaparib to that based on the PAOLA-1 study, or do you completely switch over to a PARP inhibitor? We also explored adding veliparib as an option to chemotherapy followed by veliparib maintenance based on the VELIA trial.
What is the main message to take away from all this information?
It is very important to be aware of all the new studies that are being presented. We saw 3 studies presented at the 2019 ESMO Congress at the same time, and we were able to evaluate all of these results together. Not all of these drugs are currently FDA approved for this indication, so although we have these trials, it doesn’t mean you can just start out and offer that to your patient.
What was really neat about the presentation of all 3 trials was the differences between them in terms of the patient populations [examined], the drug combinations evaluated, and the different drugs used. We are able to synthesize this information to determine what the best option is for our patients. The bottom-line is that in select patient populations, specifically those who have [a germline or somatic] mutation of BRCA1/2 or women with HRD, based on the PRIMA trial, there appears to be a benefit with PARP inhibitors. In patients who do not have these biomarkers, I am not sure where we stand yet. We need to evaluate the data critically and look at the benefit achieved for patients. We need to then have a real discussion about the toxicities, such as the adverse events associated with the drugs as well as the financial toxicities.
Were any other notable presentations made at the 2020 SGO Winter Meeting regarding PARP inhibitors?
At the meeting, Whitney N. Goldsberry, MD, of the University of Alabama at Birmingham, gave a fabulous presentation on her abstract. She had been researching financial issues that are very important in prescribing any type of maintenance in this setting, but she was particularly exploring PARP inhibitor maintenance therapy. What was so important from her research was that it underscored the need for patients and providers to be aware of financial assistance programs that are available. With the use of these financial assistance programs, the financial toxicity [associated with these agents] can be reduced. I believe that reducing such toxicities can also reduce stress for our patients. It is very important that we know this.