BRCA Mutations, HRD Status Drive PARP Inhibitor Selection in Ovarian Cancer Maintenance

Without head-to-head comparative data, testing for the presence of BRCA mutations and homologous recombination–deficient (HRD) status remain the optimal ways to select between the PARP inhibitors olaparib (Lynparza), niraparib (Zejula), or rucaparib (Rubraca) for maintenance treatment of patients with ovarian cancer, according to Bobbie J. Rimel, MD.

“All patients with ovarian cancer should receive BRCA genetic testing and an HRD assessment to allow clinicians to best counsel patients on the magnitude of benefit that they are likely to receive from up-front PARP inhibitor [maintenance] therapy and to provide families with the opportunity to get cascade testing, hopefully preventing cancers in the future,” said Rimel, who participated in an OncLive^® Institutional Perspectives in Cancer (IPC) webinar on ovarian cancer care.

In an interview with OncLive^®, Rimel, an assistant professor of Obstetrics and Gynecology at Cedars-Sinai Medical Center, discussed how PARP inhibitors are deployed across different treatment settings of ovarian cancer, the recent market withdrawal of PARP inhibitors in later-line indications, and ongoing research efforts at Cedars-Sinai Medical Center for patients with ovarian cancer.

OncLive^®: Could you expand on the focus of your presentation at the IPC event?

Rimel: My discussion mostly centered on the use of PARP inhibitors in up-front maintenance for patients with ovarian cancer after they have completed their up-front chemotherapy. We also looked at data on PARP inhibitors used in second-line maintenance after a platinum-sensitive recurrence and the completion of platinum-doublet chemotherapy. Finally, we discussed the data for the use of PARP inhibitors as treatment in later lines of therapy and the recent withdrawals from the market of the PARP inhibitors in that space.

Without head-to-head trials of PARP inhibitors, how have the available data influenced the selection of PARP inhibitors for treatment in the primary maintenance, secondary maintenance, and recurrent settings?

There are no direct comparison studies, and there probably will not be [in the future]. However, some of the studies allow us to interpret them for specific populations. Specifically, the phase 3 SOLO-1 trial [NCT01844986] looked at the use of olaparib in primary maintenance for [patients with] BRCA germline mutations or BRCA somatic mutations. For that study, we feel confident that the use of olaparib in the [BRCA-mutated] population provides a significant [progression-free survival (PFS)] benefit, [with initial findings from the trial] showing a hazard ratio of 0.3 [for olaparib vs placebo]. It is a great idea to use olaparib in that population, and we feel confident that olaparib is a drug that has a clear indication.

For patients who have HRD ovarian cancer as defined by the approved companion diagnostic test, we can use niraparib or olaparib. If we use olaparib, that indication is given in combination with bevacizumab [Avastin], based on the [phase 3] PAOLA-1 trial [NCT02477644].

The [phase 3] PRIMA trial [NCT02655016] provided data with niraparib in both patients who were HRD and those with homologous recombination–proficient [HRP] disease. Only PRIMA showed that there was any benefit for patients with HRP with a PARP inhibitor used as primary maintenance.

When we are thinking about [patients who are] HRP, we only have one PARP inhibitor, niraparib, that showed a benefit. For HRD, we have olaparib with bevacizumab, niraparib, or rucaparib. In the HRD setting, we have 3 options that are all FDA approved.

What is the importance of stratifying patients based on HRD, HRP, and BRCA mutation status?

Stratifying patients for BRCA mutations [allows us to] offer PARP inhibition in maintenance therapy and [identify patients] for cascade testing. When [we encounter] a patient that has a BRCA mutation, we have the ability to offer her relatives [cascade] testing and do appropriate cancer screening prevention, which is a wonderful thing for the patient's family and community.

For HRD, that test is valuable in helping us understand what the patient’s magnitude of benefit is likely to be when treated with a PARP inhibitor. There is a huge difference for the projected PFS for patients treated with a PARP inhibitor in maintenance who are HRD vs HRP. That is helpful in helping patients understand whether they want to take on the potential adverse effects of [receiving] a PARP inhibitor as maintenance therapy.

What is the relationship between recurrence on PARP inhibitors and sensitivity to platinum-based chemotherapy? How does this affect treatment planning?

[Although we do not have] resounding, clear evidence, recurrence on PARP inhibitors seems to make patients less likely to be sensitive to their next line of platinum chemotherapy. Again, that is not completely settled, but that is something that we are worried about. If you think about the mechanisms of resistance that would evolve in exposure to PARP inhibition, [this makes sense]. PARP inhibition is when [patients] are not utilizing their DNA damage–repair machinery in its most ideal fashion, and the mechanisms of resistance around that are likely similar to the mechanisms of resistance that would develop to platinum chemotherapy, where DNA damage repair is also a mechanism of action.

That is what we are seeing and what we are beginning to understand in the data, but it is still early days [for understanding the relationship between PARP inhibition and platinum sensitivity].

What should physicians know about the withdrawn indications for PARP inhibitors?

It is important to keep updated with what the withdrawn indications are and ensure that the patients that are currently in your practice who are using PARP inhibitors in that indication are informed.

Even outside of a clinical trial, we should inform our patients of emerging safety data for the drugs that we use and obtain a reconsent that they still wish to continue. Some patients with these emerging data may wish to stop their PARP inhibitor, especially if they are in a setting of remission. They may wish to stop it, hoping to avert any of the potential concerns that we see emerging in the data.

Is there any ongoing or planned research happening at Cedars-Sinai that you would like to highlight?

One of the projects that we have ongoing is the Gilda Radner Hereditary Cancer Program, which is a large longitudinal study looking at patients who have a BRCA1/2 mutation. This study was started by Beth Y. Karlan, MD, formerly of Cedars-Sinai and now of UCLA Health, and it has continued at Cedars-Sinai. We are excited to be able to offer this study to patients, and now that the study is fully digital, patients who do not see us in clinic can participate.

Hopefully from this large dataset, we can continue to investigate markers for whether a patient is likely to develop a cancer, and potentially [identify] other options for prevention or control.