Over the past decade, PARP inhibitors have emerged as the main trend in the ovarian cancer treatment market. And two drugs -- Lynparza (olaparib) and Zejula (niraparib) -- divide the market.

First runner Lynparza drew attention by treating patients with specific genetic mutations. In contrast, latecomer Zejula rapidly expands market share by confirming its effects in all patients regardless of genetic mutations and proving “all-comer” indications.

However, Zejula’s “all-comer” indications as the secondary maintenance therapy for ovarian cancer sharply narrowed to “gBRCA+” patients in the U.S. last November.

Despite the U.S. Food and Drug Administration’s move, the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA) recognized Zejula’s treatment benefits in the secondary maintenance therapy of ovarian cancer, recommending maintaining the current indication.

Against this backdrop, Korea Biomedical Review met with Han Ji-soo, senior brand manager at Takeda Korea’s anticancer business unit, who has been responsible for the Zejula brand since 2019 when the drug won domestic approval and was released to the market, to listen to the company’s position on the latest controversy over indication changes and the drug’s role and outlook regarding Korean ovarian cancer patients.

Question: What’s the status of Zejula in the domestic PARP inhibitor market?

Answer: Zejula made its debut in the domestic market in 2019. So, this is the fourth year. Zejula became the leader in the domestic ovarian cancer PARP market in 2021, two years after its debut. It has attained a significant outcome in a very short period since its introduction in the Korean market.

Q: Zejula has the advantage of having all-comer indications as the primary and secondary maintenance therapy of ovarian cancer. However, considering the current standard primary treatment is the combination therapy of chemotherapy and bevacizumab, Zejula’s rapid market share increase is an amazing accomplishment.

A: In treating ovarian cancer, the primary post-operative treatment is one of the two options – paclitaxel + carboplatin + bevacizumab or paclitaxel + carboplatin. However, more than 80 percent of Korean ovarian cancer patients receive the combination therapy of paclitaxel and carboplatin without bevacizumab to receive Zejula maintenance therapy without restrictions after getting primary anticancer treatment. However, as the reimbursement standards for bevacizumab are limited to the high-risk groups of phases 3b-3c or 4, other patients can use only paclitaxel + carboplatin combo therapy with bevacizumab.

Q: Recently, an issue was raised concerning Zejula’s indication for secondary maintenance treatment. However, Europe expressed a different position from the U.S. How should we interpret this? And we are curious about what effects the recent issue will have on Korean patients.

A: The indication change in the U.S. was made based on the FDA’s review of the overall survival (OS), the secondary endpoint of the NOVA study (the basis for approving Zejula’s indication as secondary or more maintenance therapy). It was because the risk rate against final OS was 1.06 in patients without gBRCA mutations. However, the key point is the NOVA study was a study that set progression-free survival (PGS), not OS, as the primary endpoint. Moreover, the gBRCA patients were not appropriately designed to certify OS, and the number of patients in this cohort was also very small.

Above all, the current risk ratio cannot be said to represent the pertinent patient group in a situation where various confounding variables intervened. A look at the OS outcomes of subgroups belonging to each cohort, some patient groups with poorer prognoses showed more favorable results. Such results suggested many confounding variables in the clinical trials, and the study results and their analyses could be uncertain.

Europe reexamined its approval, considering these points sufficiently. As a result, the EMA’s CHMP issued its opinion to maintain Zejula’s benefits favorably and without any changes, regardless of the NOVA study’s final OS results. Furthermore, it concluded that there are no changes in Zejula’s indications within Europe. Our company also discusses closely with the health authorities while prioritizing patients’ treatment access.

Q: What do you think is Zejula’s role in treating Korean ovarian cancer patients as the brand’s manager?

A: Zejula still has great potential. Jejula’s greatest feature is it can be used regardless of biomarkers, such as BRCA genes or HRD. It provides, in particular, long-term treatment benefits for BRCA-mutated or HRD+ ovarian cancer patients. According to the PRIMA study, the basis for its indication as primary maintenance treatment, it reduced disease progression and death risks by 60 percent in the BRCA patient group and by 57 percent in the HRD+ patient group. Such results could be confirmed in the PRIME study targeting Chinese patients. As presented at the SGO Annual Meeting on Women’s Cancer in 2022 (SGO 2022), Zejula showed significant progression-free survival improvement as the primary maintenance therapy for BRCA-mutated and HRD+ patients. That confirmed Zejula’s sufficient treatment effects and safety as the primary maintenance therapy for Asian patients.

Besides, Zejula is the only PARP inhibitor in Korea, which is administered only once a day. Ovarian cancer patients are mostly in their 50s and 60s and even older and usually take other drugs due to chronic diseases, including diabetes and hypertension. Zejula has low interactions with other drugs and can be administered easily and simply in patients who already take many other medicines, reducing their psychological burdens. Even if patients don’t have chronic diseases, they have only to take one tablet a day, so they don't have to keep reminding themselves that they're "cancer patients." This is the feedback I received directly from patients.

Lastly and most importantly, Zejula’s strength is its insurance benefits. Zejula has received insurance coverage for the primary maintenance therapy of BRCA-mutated ovarian cancer patients since October 2021, regardless of its administration period, or, in other words, “until the disease is cured.” Patients don’t have to shoulder all burdens after the first two years, as are the cases of other drugs. In addition, the drug provides the significant advantage of sharply lighter financial burdens as patients have only to pay 5 percent of drug prices even after two or three years pass.

Q: We also like to know whether Zejula could provide broader treatment benefits for Korean ovarian cancer patients.

A: Currently, Zejula’s insurance benefits as the primary maintenance therapy of ovarian cancer are limited to BRCAQ-mutated patients. Therefore, our company has been striving hard to improve treatment access for patients without BRCA mutation. In February, the Cancer Disease Deliberation Committee approved expanding reimbursement for Zejula’s primary maintenance therapy for HRD+ patients. I want to emphasize that it meant Zejula’s clinical data on HRD+ patients were accepted as a significant basis. It is especially significant because the insurance benefits, currently given to only BRCA-mutated patients accounting for only 20 percent of total ovarian cancer patients, will be expanded to HRD+ patients, representing about 50 percent of the total. In addition, the company is operating a patient support program to prevent them from giving up treatment for financial reasons.

Q: As the brand manager, do you have some personal aspirations or messages on behalf of your company?

A: Zejula has landed softly on the domestic ovarian cancer PARP inhibitor market. However, many issues remain to be tackled to improve patients’ access. As noted earlier, we will go all out to provide help by expanding treatment access for ovarian cancer patients without BRCA mutations. Takeda Korea prioritizes realizing patient-oriented principles by placing patients at the center of its business. We at the Zejula team will also make ceaseless efforts as reliable partners of patients and medical workers as we do now.