PARP Inhibitors Have ‘Clear Benefit’ for Patients With Ovarian Cancer and BRCA Mutations, but When and at What Cost?

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Elizabeth M. Swisher, MD

Haller J. Smith, MD

The response rate decreases with increasing number of prior therapies. So why would we want to wait until the fourth line to treat our mutation carriers.

—Elizabeth M. Swisher, MD

PARP inhibitors offer a promising alternative for targeted therapy in ovarian cancer” and have “clear benefit in BRCA-mutation carriers,” but questions remain about when is the best time to use them and the cost-effectiveness of maintenance therapy, Elizabeth M. Swisher, MD, of the University of Washington in Seattle, said at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in Chicago. Using inhibitors of poly (ADP-ribose) polymerase (PARP) enzymes in combination with other targeted therapies, as well as chemotherapy, “definitely” has the potential, she added, “to make PARP inhibitors even more effective.”

Dr. Swisher’s comments followed presentations on olaparib (Lynparza) monotherapy for patients with advanced relapsed ovarian cancer and the use of olaparib as maintenance therapy. Olaparib was approved by the U.S. Food and Drug Administration in 2014 for treatment of patients with advanced ovarian cancer and germline BRCA1/2 mutations who have received three or more prior lines of chemotherapy. In Europe, olaparib is approved “for maintenance therapy for platinum-sensitive relapse following chemotherapy in either germline or somatic BRCA mutations,” Dr. Swisher noted. “So the approval indications are quite different.”

Durable Responses in Relapsed Patients

Pooled analysis of six phase I and II olaparib trials found that patients with relapsed ovarian cancer and germline BRCA1/2 mutations experienced durable responses of around 8 months and that the durable response rate was not reduced for patients who had received three or more lines of prior chemotherapy. The analysis “evaluated the efficacy and safety of olaparib in this patient population from completed monotherapy trials, including in the subgroup of patients who had received at least three prior lines of chemotherapy,” according to Ursula A. Matulonis, MD, of Dana-Farber Cancer Center, Boston, who presented the results.

Among patients with measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 criteria, demographics and baseline characteristics were similar for the overall population of 273 patients and the 205 patients who had received at least three prior lines of chemotherapy. All patients received olaparib 400 mg in capsule formulation twice daily.

Response Declined With More Prior Therapies

The overall response rate was 36% vs 31% for the more heavily treated patients, Dr. Matulonis reported. There was a gradual decline in overall response rate with increasing lines of chemotherapy, she added.

“As Dr. Matulonis demonstrated, the response rate decreases with increasing number of prior therapies,” Dr. Swisher noted. “So why would we want to wait until the fourth line to treat our mutation carriers?” She said that many physicians probably have been faced with situations where they think patients might benefit from olaparib but “need to fail a couple more lines of chemotherapy first.”

In addition, she said, “we all know that later in the disease course, gastrointestinal symptoms become more prominent, and an oral drug may not be tolerated. So we might lose the opportunity to treat these patients with these drugs.”

In the pooled analysis, grade ≥ 3 adverse events occurred in 50% of the overall population and 54% of the subgroup. Serious adverse events occurred in 30% of all patients and 34% of the subgroups. All eight of the patients (3%) with an adverse event leading to death had received at least three lines of chemotherapy, but none of those adverse events (sepsis, intestinal perforation, suture rupture, acute leukemia, cerebrovascular accident, chronic obstructive pulmonary disease, and pulmonary embolism) was considered causally related to use of olaparib. The most common adverse events of all grades were nausea (65%), fatigue (61%), and vomiting (39%).

Maintenance Therapy With PARP Inhibitors

“Maintenance therapy for ovarian cancer has been very exciting,” Dr. Swisher stated. “Companies have invested heavily into maintenance therapy trials” with four PARP inhibitors, she added. In addition to olaparib, veliparib, rucaparib, and niraparib are in phase III maintenance trials for ovarian cancer.

In these trials, “the patient either gets the PARP inhibitor or placebo, and then the time to subsequent progression is the primary outcome, as it was in study 19,” Dr. Swisher said. That study found that maintenance therapy with olaparib extended progression-free survival in patients with advanced ovarian cancer and BRCA mutations.

Olaparib trials are “concentrating only on cases with BRCA mutations, whether germline or somatic, whereas the other three drugs have studies that are open both in the primary and relapsed setting for cases that are high-grade serous or endometrioid, and patients may have or not have BRCA mutations,” Dr. Swisher reported. “Predictors of response (and resistance) other than BRCA mutations are needed,” Dr. Swisher noted.

What Do Patients Really Want?

“Patients really want extension of life and also time off treatment, especially when that treatment involves significant side effects,” Dr. Swisher said. Thus, maintenance therapy could be used to postpone the time until subsequent chemotherapy is needed. That is “a very important endpoint,” Dr. Swisher said. “I think we can all agree that delaying chemotherapy is an important clinical incentive.”

However, there is some concern that using a PARP inhibitor as maintenance therapy might lead to chemoresistance, and some maintenance trials are looking at second subsequent chemotherapy. “That time to second subsequent chemotherapy can reflect whether or not PARP inhibitor maintenance generates chemoresistance,” Dr. Swisher said.

For example, if a patient who gets a PARP inhibitor then progresses and receives chemotherapy, but now that chemotherapy doesn’t work as well, the patient will need a different chemotherapy regimen sooner than if the patient didn’t get PARP inhibitor maintenance therapy, had a good response to subsequent chemotherapy, and was in remission again. In yet another scenario, starting a PARP inhibitor at the time of disease progression could actually end up further delaying the time to next chemotherapy and may be a more cost-effective approach.

‘Burning Questions’ Remain

“So is it better to use a PARP inhibitor in maintenance or actually at the time of relapse? If we use it as maintenance, is it in the primary setting or the recurrent setting?” These two are among the “burning questions that we still need to answer about PARP inhibitor therapy in ovarian cancer,” Dr. Swisher said.

Other questions center on assessing cost-effectiveness, determining a synergistic combination of PARP inhibitors with biologics or chemotherapy, developing tests to best define BRCA-like cancers that will respond to PARP inhibitors, and combining PARP inhibitors with other therapies that target DNA repair. This could “potentially extend PARP inhibitor therapy to cancers that are proficient in homologous recombination or cancers that have intact DNA repair,” Dr. Swisher said.

“We know that ovarian cancers that are proficient in homologous recombination are not sensitive to PARP inhibitors,” Dr. Swisher explained. “Even ­BRCA-mutated ovarian cancers eventually develop resistance to PARP inhibitors, and much of that is through restoration of DNA repair and increase of homologous recombination. So new drugs that inhibit homologous recombination could be combined with PARP inhibitors.” In that scenario, an agent that inhibits homologous recombination could be used to render an ovarian cancer proficient in homologous recombination deficient in homologous recombination, which would allow a PARP inhibitor to be synthetically lethal to that cancer. “There is definitely a lot of potential to make PARP inhibitors even more effective,” Dr. Swisher concluded.

Cost of Maintenance Therapy

Cost issues associated with olaparib maintenance therapy were tackled in a separate presentation by Haller J. Smith, MD, and colleagues at the University of Alabama at Birmingham. They found that at an estimated cost of $7,000 per month for olaparib maintenance therapy is not cost-effective. [Editors note: The authors created the model for their study prior to olaparib being approved by the FDA; therefore, the $7,000 cost they used in the original model was an estimate based on other targeted agents. The actual cost of olaparib is $13,440 per month.]

The study compared the cost-effectiveness of olaparib maintenance therapy with observation in patients with platinum-sensitive recurrent ovarian cancer who had received six cycles of paclitaxel and carboplatin. As explained in the study abstract, “Cost-effectiveness ratios and incremental cost-effectiveness ratios per progression-free life-year saved were calculated for patients with BRCA mutations and for patients with wild-type BRCA.” The researchers estimated that 5,549 patients were diagnosed with platinum-sensitive cancer in the United States and assumed a BRCA germline mutation rate of 20%.

“Assuming a cost similar to that of other oral targeted agents, olaparib maintenance therapy would result in an increase in cost of $85.8 million compared with observation for patients with platinum-sensitive recurrent ovarian cancer and a deleterious BRCA mutation. Maintenance therapy with olaparib is not cost-effective, with an incremental cost-effectiveness ratio of $135,672. To achieve an incremental cost-effectiveness ratio of less than $50,000, the cost of olaparib should be $2,500 or less per month,” the authors concluded. “For wild-type BRCA patients, maintenance therapy with olaparib is unlikely ever to be cost-effective.” ■

Disclosure: Dr. Matulonis has received research funding from AstraZeneca, is on advisory boards for ImmunoGen and Genentech, and is a member of the speakers bureau for AstraZeneca. Drs. Swisher and Smith reported no potential conflicts of interest.