Since June, manufacturers of the three FDA-approved poly (ADP-ribose) polymerase (PARP) inhibitors have withdrawn their indications in the later line treatment setting for ovarian cancer. Payers should be reviewing their utilization management criteria to make sure they are covering the drugs in the appropriate setting, advises one industry expert.
In a Form 8-K filed with the U.S. Securities and Exchange Commission on June 16, Clovis Oncology, Inc. said it was voluntarily withdrawing the FDA approval for Rubraca (rucaparib) for the treatment of BRCA-mutated ovarian cancer after at least two chemotherapies based on overall survival (OS) data from the ARIEL4 clinical trial. The company also disclosed that it had requested withdrawal of that indication in Europe. The drug’s indications for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy and for the treatment of adults with a deleterious BRCA mutation-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy, the latter of which has accelerated approval, remain on its label.
In a Form 10-Q filed with the SEC on Nov. 9, Clovis disclosed that due to its cash, cash equivalents and sales of Rubraca — as well as FDA scrutiny of later line ovarian cancer indications for the PARP inhibitors — it “will not have enough sufficient liquidity to maintain our operations beyond January 2023” and, thus, “a potential bankruptcy filing in the very near term looks increasingly probable.” The company also said that it let go 115 employees on Nov. 7. Rubraca is the company's only marketed product.
In August, AstraZeneca and Merck & Co., Inc. notified health care professionals that they were voluntarily withdrawing the FDA approval for Lynparza (olaparib) for the treatment of adults with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with at least three lines of chemotherapy based on OS data from its SOLO3 trial. The drug still has three other ovarian cancer indications in earlier line settings on its label, as well as ones for certain breast, pancreatic and prostate cancers.
Finally, in September, GSK notified health care providers that it had voluntarily withdrawn the approval for Zejula (niraparib) for the treatment of adults with advanced ovarian, fallopian tube or primary peritoneal cancer who have been treated with at least three chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status due to OS rates in the QUADRA study. The drug still has two indications for early use in ovarian cancer on its label: for the maintenance treatment of adults with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy and for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
However, GSK was hit with potentially more bad news one week later when the FDA said in a Federal Register notice published on Sept. 22 that on Nov. 22, its Oncologic Drugs Advisory Committee (ODAC) would discuss Zejula’s indication for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Specifically, ODAC plans to assess the final OS data from the NOVA trial and whether this indication should remain on the drug’s label.
“PARP inhibitors, which had emerged as one of the most common targeted therapies for unresectable ovarian cancer, may potentially increase death risk in patients who experienced several chemotherapies, causing manufacturers to withdraw their respective indications,” observes Andy Szczotka, Pharm.D., chief pharmacy officer of AscellaHealth.
Rubraca’s ARIEL4 study showed that the drug had “an increased risk of death over chemotherapy in patients with third or later line ovarian cancer (median overall survival of 19.4 months compared to 25.4 months), despite showing a progression free survival,” he points out.
In Lynparza’s SOLO3 trial, “despite showing there was no significant difference in OS between Lynparza and chemotherapy (34.9 months in Lynparza arm vs. 32.9 months in chemotherapy arm) in patients who received two or more lines of prior chemotherapy, in a subgroup analysis of patients who received at least two lines of therapy, 65.2% of those who received Lynparza died compared to 52.3% on chemotherapy. For patients who received three or more prior lines of chemotherapy, 70.0% of the Lynparza treated patients died compared to 54.8% of the chemotherapy assigned arm.”
And in the Zejula withdrawal, GSK “stated that the indication withdrawal was made in consultation with the FDA based on a totality of information from PARP inhibitors in the late-line treatment setting in ovarian cancer,” says Szczotka. “A potential detrimental effect on OS was observed with other PARP inhibitors in two different independent, randomized, active-controlled clinical trials.”
According to Szczotka, “while these indication withdrawals do not affect other approved uses for these products, there may be a safety signal without added significant clinical efficacy with the use of the PARP inhibitors in this specific patient population.”
It is not known, he tells AIS Health, a division of MMIT, why the safety signals are in later lines of therapy for ovarian cancer. “It can be speculated that there may be many contributing factors that are leading to higher death rates seen in the reported clinical studies. Clinical studies will need to be conducted or the current trial data further analyzed to ensure that this safety signal is limited to the later lines of therapy and is not seen with earlier treatment or to identify specific patient populations where the higher risk is identified.”
Asked whether there should be concern over the drugs’ use in prostate cancer, Szczotka replies that “while the safety signals seen with late-stage ovarian cancer have not yet been seen in the clinical studies or use in prostate cancer, there will be increased scrutiny of the clinical data to ensure that similar effects are not seen. While the patient populations are different, as well as their place in treatment protocols, for these cancers the potential exists for [possible] crossover effect of the PARP inhibitors on safety. Review of available safety data by the FDA and respective manufacturers to ensure that the same safety signals are not present will enable the continued safe use of PARP inhibitors for prostate cancer for appropriate patients.”
Payers, he says, “will need to review their current guidelines and utilization management criteria for ovarian cancer to ensure that these PARP inhibitors are being used appropriately and not for these later lines of therapy due to the safety signals. Continued monitoring of the clinical data and upcoming FDA reviews will provide additional information that will help guide appropriate use of the PARP inhibitors.”
Szczotka points out that Clovis has submitted a supplemental new drug application (sNDA) for Rubraca for the “frontline maintenance treatment for advanced ovarian cancer irrespective of biomarker status [in people] who have responded to first-line platinum-based chemotherapy. The sNDA is based on the ATHENA trial, which found that Rubraca improved progression free survival (PFS), irrespective of HRD status. Rubraca lowered the risk of disease progression or death by 53% (Rubraca PFS was 28.7 months as compared to 11.3 months for the placebo arm). The primary endpoint of the ATHENA trial was the PFS results, and this data may support the use of Rubraca as a potential therapy option for first-line maintenance treatment for ovarian cancer. FDA review and potential action is anticipated in 2023.”
Of the upcoming ODAC meeting on Zejula, “the NOVA trial met the primary endpoint of PFS in various group cohorts, demonstrating a statistically significant and clinically meaningful treatment effect, regardless of biomarker status,” notes Szczotka. “These PFS results served as the primary basis for the FDA approval. Overall survival was a secondary endpoint. Restricted mean survival time analyses for OS up to 72 months in the Zejula and placebo arms were 45.9 months with Zejula in the gBRCAm cohort (vs. 43.2 months with placebo) and 38.5 months with Zejula in the non-gBRCAm cohort (vs 39.1 months with placebo). The NOVA study was not powered for OS, so it will be interesting to see the Advisory Committee’s findings and recommendations of this submitted OS data and any impact on the current indication.”
Contact Szczotka via Caroline Chambers at firstname.lastname@example.org.
By Angela Maas