Weighing Risks and Benefits Is Critical With Second-Line Maintenance PARP Inhibition in Ovarian Cancer

Allison M. Puechlm, MD

The introduction of PARP inhibitors to the second-line maintenance setting has allowed some patients with recurrent ovarian cancer to derive prolonged progression-free survival (PFS), while being spared chemotherapy-related toxicities, said Allison M. Puechl, MD. However, choosing between the 3 approved PARP inhibitors, olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca), remains a significant challenge.

“Second-line maintenance therapy is going to be incredibly important for patients because we know that once a patient with ovarian cancer recurs, their disease is incurable,” said Puechl. “Second-line maintenance therapy should be considered for these patients because it can [provide] meaningful time that is largely free of [chemotherapy-related] toxicities.”

An additional nuance in utilizing maintenance therapy with PARP inhibitors is that each agent has FDA indications in settings other than second-line maintenance, explained Puechl. Moreover, the financial burden that these drugs can pose to patients signals a need to weigh the potential benefits and risks of second-line maintenance for patients.

“Discussing second-line maintenance therapy with patients early is an important concept, specifically regarding the PFS benefit that the studies have shown.” Puechl added. “Then, patients can weigh that with the toxicities [associated with PARP inhibitors] and the financial toxicities [these drugs can pose].”

Future research efforts are underway to try to identify combination regimens with dual PARP inhibition, immunotherapy, or chemotherapy that may provide longer-term PFS benefit than single-agent PARP inhibition.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on ovarian cancer, Puechl, a gynecologic oncologist at Levine Cancer Institute, Atrium Health, discussed the role of second-line maintenance therapy in patients with recurrent ovarian cancer and considerations that may limit the accessibility of PARP inhibitors in this space.

OncLive®: Are all patients eligible to receive second-line maintenance therapy with a PARP inhibitor?

Puechl: Three PARP inhibitors: olaparib, niraparib, and rucaparib, are FDA approved in the second-line maintenance setting. It is important to know that all 3 of these drugs are not biomarker restricted. Meaning, they are approved for BRCA-mutated and non–BRCA-mutated germline and somatic tumors, as well as homologous recombination deficient (HRD) and proficient tumors. Basically, they are approved for all-comers.

[Patients with recurrent ovarian cancer] are often on several lines of systemic chemotherapy, which comes with a lot of adverse effects and poor quality of life. If we can do anything to extend an interval of time that the patient does not have to be on systemic chemotherapy, that becomes really meaningful to the patient who recurs. That is why the use of PARP inhibitors in the second-line maintenance setting becomes so important to patients. Patients typically feel better on PARP inhibitors compared with systemic chemotherapy. If a PARP inhibitor can be used to lengthen the amount of time that a patient has before starting back on systemic chemotherapy, it becomes really beneficial.

What PARP inhibitors or other second-line maintenance strategies are in the pipeline that look promising?

All kinds of phase 1 clinical trials are coming down the pipeline. Also, trials looking at combination [regimens], such as PARP inhibition with immunotherapy, are coming. That will be in the future and is something to keep an eye out for. If we combine PARP inhibition with immunotherapy or other chemotherapeutic agents, what is the benefit to patients and how does that affect long-term survival and PFS?

How are you choosing between the 3 PARP inhibitors without head-to-head comparative data?

That is the million-dollar question right now in the ovarian cancer world: How do we choose between the 3 PARP inhibitors? One of the most important things is that we can’t do cross-trial comparisons because the inclusion criteria are different for each trial. Comparing PFS is not fair between drugs.

Because of this, a lot of other gynecologic oncologists, and myself, are prescribing what they are most comfortable with or looking at the patient’s labs and toxicities. All the [PARP inhibitors] can cause fatigue, nausea, vomiting, and generalized malaise, so that is something to consider. Regarding patient labs, niraparib is more likely to cause thrombocytopenia. If a patient has struggled with thrombocytopenia in the past, I might not pick niraparib. However, I have also found that the once-a-day dosing with niraparib has been beneficial to patients compared with twice-a-day dosing. It is a little bit patient specific—knowing what their labs have looked like in the past—but it is also important to talk to the patient about dosing and see how they tolerate one PARP inhibitor before switching them to a different drug.

Does the fact that these agents have other FDA-approved indications in ovarian cancer factor into second-line maintenance therapy selection?

That is exactly right; all of the PARP inhibitors have been approved for treatment later on in the treatment course. We know that patients are more likely to benefit from second-line maintenance therapy if they have platinum-sensitive disease, so I would be more apt to use a maintenance therapy in those patients.

If we’re using PARP inhibitors as a treatment regimen later on, we still do not have great data yet about giving PARP inhibitors after a patient has already received a PARP inhibitor. That is something that we weigh [when considering second-line maintenance therapy].

Also, [we consider] the patient’s functional status. If I am comparing treatment with a PARP inhibitor with a systemic chemotherapy, I am more apt to choose a PARP inhibitor because they will probably be better tolerated. [PARP inhibitors] are nice additions to have in our toolbox for treatment of certain patients.

Do you anticipate readouts of comparative trials with PARP inhibitors, or has PARP after PARP become the focus of ongoing research efforts?

I am not aware of head-to-head comparison trials, but a lot of studies are looking at the concept of PARP after PARP. That is going to be one of the bigger things coming that we are looking forward to. What happens if patients who have been on a PARP inhibitor recur and want to be treated again with a PARP inhibitor? Are we seeing any benefit with that?

Alternatively, is there an effect if the patient receives a certain type of chemotherapy agent before they receive a PARP inhibitor a second time? We are going to find out more information about timing of treatment and subsequent therapies.

Beyond the challenges of treatment selection, what are some of the other hurdles in the second-line maintenance setting that need to be overcome?

Beyond choose between the 3 agents, one of the biggest questions is: What do we do with our patients who have non-BRCA–mutated or homologous recombination deficient (HRD)–proficient disease? These patients typically have the least amount of response to PARP inhibitors. Though, they can still [derive] about a 3-month benefit from second-line maintenance therapy.

One of the challenging things as a physician is having these conversations with my patients and weighing the pros and cons of PARP inhibition in the second-line maintenance setting. Patients could potentially get 3 months of PFS, but is that worth it to further delay chemotherapy for those 3 months? These medications are costly, so we also have to talk to the patient about financial toxicity. What are the pros and cons of financial toxicity for the group of patients with non–BRCA-mutated, HRD-proficient disease who don’t have the best response [to PARP inhibition]?

If we are able to delay chemotherapy by 3 months and provide 3 months of survival that is pretty well tolerated on a PARP inhibitor, that is appealing to the patients who have recurrent disease and are looking at being off-and-on treatment for the remainder of their lives.