Safety issues: Another company withdrew its indication for PARP inhibitors

Because of safety issues, to what extent can this year's PARP inhibitors "collapse"?

On November 11, GSK announced for the second time that it withdrew some indications of the PARP inhibitor Zejula, which will be used only in patients with ovarian cancer with harmful and suspected harmful germline BRCA mutations in the second line
.

This decision was based on a review of the final overall survival (OS) analysis of the ENGOT-OV16/NOVA Phase III trial
.
In the final results, the hazard ratio (HR) for the OS secondary endpoint in the non-BRCA mutation patient (non-gBRCA) cohort was 1.
06 (95% CI: 0.
81-1.
37).

Zejula did not help patients with non-BRCA mutations achieve longer survival after two rounds of chemotherapy compared to placebo
.
As a result, GSK withdrew Zejula's treatment
for patients with ovarian cancer who were stable after second-line chemotherapy.

In addition, Zejula remains unchanged in the U.
S.
first-line indication for maintenance therapy
in adult patients with advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have fully or partially responded to platinum-based chemotherapy.

GSK acquired Zejula
when it acquired Tesaro for $5.
1 billion in 2018.
BIOPHARMA pE data indicates that Zejula's sales in 2021 were about $543 million, but sales fell to about $418 million
in the third quarter of this year.

Even Lynparza, the previously best-selling PARP inhibitor, has seen its sales decline recently
.
AstraZeneca's third-quarter results were lower than consensus
expectations after consulting with the FDA to withdraw Lynparza's indication for the treatment of adult patients with harmful or suspected harmful gBRCAm advanced ovarian cancer who had received three or more prior chemotherapy regimens.

What's more, in June, after the FDA reviewed the overall survival data of the Clovis Oncology and ARIEL4 trials, Rubraca was withdrawn due to the increased risk of death, and the EMA initiated a review of the indication in April, followed by the CHMP recommendation to limit the use
of Rubraca.
In the third quarter of this year following the withdrawal of the indication, Rubraca's remaining maintenance therapy for prostate cancer and recurrent ovarian epithelial, fallopian tube or primary peritoneal cancer supported sales of only $30.
7 million, down from $32.
1 million in the second quarter.

The negative news of the pillar product not only directly affected Rubraca's ability to generate revenue, but also affected Clovis' cash flow turnover, and Clovis even released the news
of impending bankruptcy.

Safety has become an inescapable issue
for PARP inhibitors.
In the combination of PARP inhibitors and chemotherapy, the limitation lies in the superposition of toxic side effects, especially hematotoxicity, such as lymphopenia
.
In terms of molecular mechanism, hematotoxicity comes from the inhibition of PARP2, but the currently marketed PARP inhibitors are not selective for PARP1 and PARP2, which is the root cause
of increased mortality risk.

From a clinical point of view, the 2022 NCCN guidelines have been updated five times, and the reasons for this have changed a lot, or it may be due to its strong toxic side effects and the successive withdrawal of pharmaceutical companies
' PARP inhibitor indications.

Although each company emphasizes that withdrawing one indication will not affect other indications of the drug, the increased FDA review of PARP inhibitors, and safety issues that are not addressed at this stage, may lead some physicians to reduce the use of
PARP inhibitors in the clinic.

This is bound to directly impact the growth of
the PARP inhibitor market.
Andrew Berens, an analyst at SVB Securities, wrote in a Nov.
10 report: "The effect of PARP classes on overall survival outside BRCA patients treated for late-line ovarian cancer is a key regulatory concern and will negatively affect
the sales of the drug.
" While PARP inhibitor drugs are already being studied to shift to the early treatment line for ovarian cancer patients, concerns about their safety could affect widespread use
.
”

References:

1.
Under FDA pressure, GSK limits use of ovarian cancer drug； BIOPHARMA pE

2.
The use of three PARP inhibitors increases the risk of death in ovarian cancer patients! The indications have been withdrawn!; Lilac Garden tumor time

3.
Are PARP inhibitors not fragrant? Concept stock Clovis lays off employees and is about to go bankrupt; Same as freehand

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