Janssen's Zejula Receives FDA Breakthrough Therapy Designation for mCRPC with BRCA Mutations; Under Priority Review in Mainland China

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Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, recently announced that the U.S. FDA has granted Breakthrough Therapy Designation (BTD) to Zejula (Chinese brand name: Zele; generic name: niraparib), a PARP inhibitor anticancer drug, for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 mutations who have previously received taxane chemotherapy and androgen receptor (AR)-targeted therapy. BRCA1/2 mutations represent the most common DNA repair defects (DRD) in mCRPC patients. Patients with DRDs in BRCA1/2 are at higher risk for prostate cancer development and aggressive disease.

Breakthrough Therapy Designation (BTD) is a new drug review pathway established by the FDA in 2012, designed to expedite the development and review of new drugs intended to treat serious or life-threatening diseases, where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on at least one clinically significant endpoint. Drugs granted BTD receive more intensive guidance, including from senior FDA officials, during development, ensuring that new treatment options are made available to patients in the shortest possible time.

The FDA’s granting of Breakthrough Therapy Designation (BTD) to Zejula was based on the results of the Phase II GALAHAD clinical study. This multicenter, open-label study evaluated the efficacy and safety of Zejula (300 mg, once daily) in adult patients with metastatic castration-resistant prostate cancer (mCRPC) harboring DNA damage response (DDR) gene alterations (DRD), who had experienced disease progression during or after treatment with next-generation androgen receptor-targeted therapies and docetaxel. DRD status was defined by pathogenic mutations (including homozygous deletions) in any of the following eight genes: BRCA1/2, ATM, FANCA, PALB2, CHEK2, BRIP1, and HDAC2, as determined by validated plasma analysis. The primary endpoint was objective response rate (ORR), assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The key secondary endpoint was the composite response rate (CRR), defined as achieving one or more of the following: ORR, circulating tumor cells (CTCs) <5 cells per 7.5 mL of blood, or a ≥50% reduction in prostate-specific antigen (PSA).

The data from this study were presented at the 2019 European Society for Medical Oncology (ESMO) Annual Meeting in late September. As of May 23, 2019, a total of 165 patients with metastatic castration-resistant prostate cancer (mCRPC) had been enrolled, including 81 patients with biallelic DRD mutations (46 with BRCA mutations and 35 with non-BRCA mutations). These patients had been followed up for at least 16 weeks at the time of the data cutoff. Among the 81 patients, 51 had measurable disease at baseline (29 with BRCA mutations and 22 with non-BRCA mutations). The median follow-up duration was 7.3 months for patients with BRCA mutations and 6.4 months for those with non-BRCA mutations.

Data showed that: (1) In BRCA patients, the ORR was 41%, the CRR was 63%, the median duration of objective response was 5.5 months (range: 3.5–9.2), the median radiographic progression-free survival (rPFS) was 8.2 months, and the median overall survival (OS) was 12.6 months. (2) In non-BRCA patients, objective responses were observed in 2 out of 22 patients (both with FANCA gene mutations), the CRR was 17%, and the durations of objective response were 3.8 months and 6.5 months, respectively. Regarding safety, grade 3/4 treatment-emergent adverse events were primarily hematologic—anemia (29%), thrombocytopenia (15%), and neutropenia (7%)—and these events were managed through dose interruption or adjustment.

The aforementioned data confirm that Zejula treatment demonstrates clinical response in patients with drug-refractory metastatic castration-resistant prostate cancer (mCRPC) harboring DNA damage repair defects (DRD), particularly showing durable responses in carriers of biallelic BRCA mutations.

The active pharmaceutical ingredient of Zejula is niraparib, an oral, small-molecule, highly selective poly(ADP-ribose) polymerase (PARP) inhibitor that exploits defects in DNA repair pathways to preferentially kill cancer cells. This mechanism of action endows the drug with the potential to treat a broad range of tumors characterized by DNA repair deficiencies. PARP is implicated in a wide variety of tumor types, including breast cancer, ovarian cancer, and prostate cancer. To date, four PARP inhibitors have received regulatory approval for marketing worldwide; the other three are AstraZeneca’s Lynparza (olaparib), Clovis Oncology’s Rubraca (rucaparib), and Pfizer’s Talzenna (talazoparib).

Zejula was developed by Tesaro. In April 2016, Janssen entered into a global collaboration and license agreement with Tesaro (excluding Japan), securing exclusive rights to Zejula for the treatment of prostate cancer. Currently, Janssen is conducting the Phase III MAGNITUDE clinical study to evaluate Zejula in combination with Zytiga (abiraterone acetate) and prednisone in adult patients with metastatic prostate cancer. The patient population enrolled in this study comprises individuals with earlier-stage metastatic castration-resistant prostate cancer (mCRPC) and is broader than that of the GALAHAD study. Additionally, Janssen is conducting the Phase I/II QUEST study to assess combination therapies involving Zejula in patients with mCRPC.

In the United States and the European Union, Zejula was approved in 2017 for the maintenance treatment of adult patients with recurrent ovarian cancer who are in response (partial or complete) to platinum-based chemotherapy, regardless of tumor BRCA mutation status or other biomarker status. Notably, Zejula is the first PARP inhibitor that does not require BRCA or other biomarker testing prior to initiation of therapy, thereby enabling a broader population of ovarian cancer patients to benefit from treatment.

GlaxoSmithKline acquired Tesaro for $5.1 billion in December 2018. Currently, a supplemental New Drug Application (sNDA) for Zejula is undergoing priority review by the U.S. FDA, with a decision expected this month. The sNDA seeks approval for a new indication for Zejula: the treatment of patients with advanced ovarian cancer who have received three or more prior chemotherapy regimens and whose cancer is associated with either (1) BRCA mutations, or (2) homologous recombination deficiency (HRD) and disease progression more than six months after the last platinum-based chemotherapy regimen.

Zejual is a potential best-in-class PARP inhibitor, owing to its differentiated efficacy, once-daily dosing, and superior pharmacokinetic profile, including the ability to cross the blood-brain barrier.

In late September 2016, Zai Lab and Tesaro, Inc. entered into a license agreement, granting Zai Lab the rights to Zejula in Mainland China, Hong Kong (China), and Macao (China). In the Chinese market, Zejula was approved in Hong Kong last October and in Macao this June for maintenance treatment of patients with recurrent ovarian cancer who have achieved a response to platinum-based chemotherapy. In Mainland China, the National Medical Products Administration (NMPA) accepted the new drug application for Zejula and granted it priority review status at the end of January 2019.

According to Zai Lab, despite launching two years later than Lynparza, Zejula has rapidly gained market share in Hong Kong since its launch there in October 2018. Based on IQVIA data, Zejula is currently the PARP inhibitor with the highest market share in Hong Kong, reaching 66% in the second quarter of 2019.

Reference Source:

1、Janssen Announces U.S. FDA Breakthrough Therapy Designation Granted for Niraparib for the Treatment of Metastatic Castration-Resistant Prostate Cancer2、Pre-specified interim analysis of GALAHAD: A phase

2 study of niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC and biallelic DNA repair gene defects DRD)

3、U.S. Food and Drug Administration accepts GSK’s application for ZEJULA (niraparib) in late stage ovarian cancer with priority review

4. Zai Lab Official Website