BRCA mutations and HRD status determine the selection of PARP inhibitors in the treatment of ovarian cancer

Bobbie J. Rimel, MD, discusses how PARP inhibitors are being deployed in different ovarian cancer treatment settings, the recent withdrawal of PARP inhibitors from the market in last-line indications, and ongoing research efforts in Cedars-Sinai Medical Center for patients with ovarian cancer.

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

“All patients with ovarian cancer should receive BRCA genetic testing and HRD evaluation to enable clinicians to best advise patients on the extent of benefit they are likely to receive from the initial PARP inhibitor [maintenance] therapy and provide families with the ability to undergo cascade testing, in hopes of preventing cancers in the future,” said Rimel, who participated in a Live® Institutional Perspectives in Cancer (IPC) webinar on ovarian cancer care.

In an interview with Live®Rimel, assistant professor of obstetrics and gynecology at Cedars-Sinai Medical Center, discussed how PARP inhibitors are deployed in different ovarian cancer treatment settings, the recent market withdrawal of PARP inhibitors in the indications subsequent and ongoing research efforts at Cedars-Sinai Medical Center for patients with ovarian cancer.

Live®: Could you expand on the subject of your presentation at the IPC event?

Rimel: My discussion focused primarily on the use of PARP inhibitors in the initial maintenance treatment of patients with ovarian cancer after completing their initial chemotherapy. We also reviewed data on PARP inhibitors used as second-line maintenance therapy after platinum-sensitive recurrence and completion of dual platinum-based chemotherapy. Finally, we discussed data on the use of PARP inhibitors as therapy in the latest lines of treatment and recent market withdrawals of PARP inhibitors in this space.

Without comparative trials of PARP inhibitors, how did the available data influence the selection of PARP inhibitors for treatment in primary maintenance, secondary maintenance, and recurrent settings?

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

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

The [phase 3] PRIMA trial [NCT02655016] provided data with niraparib in both patients who were DRH and in those who were homologous recombination competent [HRP] sickness. Only PRIMA showed a benefit for HRP patients with a PARP inhibitor used as primary maintenance treatment.

When we think of [patients who are] HRP, we only have one PARP inhibitor, niraparib, that has shown benefit. For HRD we have olaparib with bevacizumab, niraparib or rucaparib. Under HRD we have 3 options which are all FDA cleared.

What is the importance of stratifying patients according to HRD, HRP and BRCA state of mutation?

Stratification of patients for BRCA mutations [allows us to] offer PARP inhibition in maintenance treatment and [identify patients] for cascade testing. When [we encounter] a patient who has a BRCA mutation, we have the ability to offer his loved ones [cascade] do screening tests and do proper prevention of cancer screening, which is a wonderful thing for the patient’s family and community.

For HRD, this test is valuable because it helps us understand the magnitude of the likely benefits to the patient when treated with a PARP inhibitor. There is a huge difference for the projected PFS for patients treated with a maintenance PARP inhibitor who are HRD vs HRP. This is helpful in helping patients understand whether they want to assume the potential side 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] clear and resounding evidence, the recurrence of PARP inhibitors seems to make patients less likely to be responsive to their next line of platinum-based chemotherapy. Again, it’s not completely settled, but it’s something we’re concerned about. If you think about the resistance mechanisms that would evolve upon exposure to PARP inhibition, [this makes sense]. PARP inhibition occurs when [patients] are not using their DNA damage repair machinery in the most ideal way, and the resistance mechanisms around them are likely similar to the resistance mechanisms that would develop with platinum chemotherapy, where damage repair to DNA is also a mechanism of action.

That’s what we’re seeing and starting to understand in the data, but it’s still early days [for understanding the relationship between PARP inhibition and platinum sensitivity].

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

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

Even outside of a clinical trial, we must inform our patients of emerging safety data for the drugs we use and obtain consent that they still wish to continue. Some patients with these emerging data may wish to discontinue their PARP inhibitor, particularly if they are in remission. They may want to shut it down, hoping to avoid any potential concerns we see emerging in the data.

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

One of our ongoing projects is the Gilda Radner Hereditary Cancer Program, which is a large longitudinal study of patients with BRCA1/2 mutation. This study was initiated 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 the clinic can participate.

Hopefully, from this large data set, we can continue to study markers that help determine if a patient is at risk of developing cancer, and potentially [identify] other prevention or control options.

Martin E. Berry