[Federal Register Volume 89, Number 59 (Tuesday, March 26, 2024)]
[Notices]
[Pages 20982-20984]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-06299]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2024-N-1056]


Clovis Oncology, Inc., AstraZeneca Pharmaceuticals LP, and 
GlaxoSmithKline LLC; Withdrawal of Approval of the Indications for 
Advanced Ovarian Cancer for Poly (ADP-Ribose) Polymerase Inhibitors 
RUBRACA (Rucaparib) Tablets, LYNPARZA (Olaparib) Tablets, and ZEJULA 
(Niraparib) Capsules

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
that it is withdrawing approval of the indications for the treatment of 
adult patients with advanced ovarian cancer for poly (ADP-ribose) 
polymerase (PARP) inhibitors under three new drug applications (NDAs) 
from multiple applicants. The applicants Clovis Oncology, Inc. 
(Clovis), AstraZeneca Pharmaceuticals LP (AZ), and GlaxoSmithKline, LLC 
(GSK) have each voluntarily requested that the Agency withdraw approval 
of the indications for the treatment of adult patients with advanced 
ovarian cancer for their respective PARP inhibitors and waived their 
opportunities for hearings. Applicant and indication details are 
further discussed in SUPPLEMENTARY INFORMATION.

DATES: Approval is withdrawn as of March 26, 2024.

FOR FURTHER INFORMATION CONTACT: Kimberly Lehrfeld, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6226, Silver Spring, MD 20993-0002, 301-

[[Page 20983]]

796-3137, [email protected].

SUPPLEMENTARY INFORMATION: The PARP inhibitors and their respective 
applicants, NDA numbers, and indications being withdrawn are included 
in the following table.

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          Application No.                     Drug                  Applicant         Indication being withdrawn
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NDA 209115.........................  Rubraca (rucaparib)     Clovis Oncology, Inc.,  for the treatment of adult
                                      Tablets, equivalent     5500 Flatiron Pkwy.,    patients with a
                                      to (EQ) 200             Boulder, CO 80301.      deleterious BRCA mutation
                                      milligrams (mg) base,                           (germline and/or somatic)-
                                      EQ 250 mg base, and                             associated epithelial
                                      EQ 300 mg base.                                 ovarian, fallopian tube,
                                                                                      or primary peritoneal
                                                                                      cancer who have been
                                                                                      treated with two or more
                                                                                      chemotherapies. Select
                                                                                      patients for therapy based
                                                                                      on an FDA-approved
                                                                                      companion diagnostic for
                                                                                      RUBRACA.
NDA 208558.........................  Lynparza (197laparib)   AstraZeneca             for the treatment of adult
                                      Tablets, 100 mg and     Pharmaceuticals LP,     patients with deleterious
                                      150 mg.                 1800 Concord Pike,      or suspected deleterious
                                                              Wilmington, DE 19803.   germline BRCA-mutated
                                                                                      advanced ovarian cancer
                                                                                      who have been treated with
                                                                                      three or more prior lines
                                                                                      of chemotherapy. Select
                                                                                      patients for therapy based
                                                                                      on an FDA-approved
                                                                                      companion diagnostic for
                                                                                      LYNPARZA.
NDA 208447.........................  Zejula (niraparib)      GlaxoSmithKline, LLC,   for the treatment of adult
                                      Capsules, EQ 100 mg     2929 Walnut St.,        patients with advanced
                                      base.                   Suite 1700,             ovarian, fallopian tube,
                                                              Philadelphia, PA        or primary peritoneal
                                                              19104.                  cancer who have been
                                                                                      treated with three or more
                                                                                      prior chemotherapy
                                                                                      regimens and whose cancer
                                                                                      is associated with
                                                                                      homologous recombination
                                                                                      deficiency (HRD) positive
                                                                                      status defined by either:
                                                                                      a deleterious or
                                                                                      suspected deleterious BRCA
                                                                                      mutation, or
                                                                                      genomic
                                                                                      instability and who have
                                                                                      progressed more than 6
                                                                                      months after response to
                                                                                      the last platinum-based
                                                                                      chemotherapy.
                                                                                     Select patients for therapy
                                                                                      based on an FDA-approved
                                                                                      companion diagnostic
                                                                                      device for ZEJULA.
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I. RUBRACA (Rucaparib) Tablets

A. Application Background

    On December 19, 2016, FDA approved NDA 209115 for RUBRACA 
(rucaparib) Tablets, EQ 200 mg base, EQ 250 mg base, and EQ 300 mg 
base, for the treatment of adult patients with advanced ovarian cancer 
(see table for full indication \1\). On May 4, 2022, FDA met with 
Clovis to discuss the final results from the clinical trial entitled 
``ARIEL4 (Assessment of Rucaparib in Ovarian CancEr TriaL): A Phase 3 
Multicenter, Randomized Study of Rucaparib Versus Chemotherapy in 
Patients With Relapsed, BRCA Mutant, High Grade Epithelial Ovarian, 
Fallopian Tube, or Primary Peritoneal Cancer.'' \2\ The results 
indicated that patients in the intent-to-treat population who were 
taking rucaparib potentially had a shorter overall survival (OS) than 
patients not on rucaparib. At that meeting FDA conveyed that these 
results constituted a serious risk for patients receiving treatment 
with rucaparib. On May 10, 2022, the Agency asked Clovis, in writing, 
to voluntarily permit FDA to withdraw approval of the indication for 
the treatment of adult patients with deleterious BRCA mutation-
associated epithelial ovarian, fallopian tube or primary peritoneal 
cancer who have been treated with two or more chemotherapies, pursuant 
to Sec.  314.150(d) (21 CFR 314.150(d)) and waive its opportunity for a 
hearing. On June 1, 2022, Clovis submitted a letter requesting 
withdrawal of approval of this indication for RUBRACA (rucaparib) 
Tablets pursuant to Sec.  314.150(d) and waiving its opportunity for a 
hearing.
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    \1\ The initially approved indication was ``as monotherapy for 
the treatment of patients with deleterious BRCA mutation (germline 
and/or somatic)-associated advanced ovarian cancers [emphasis added] 
who have been treated with two or more chemotherapies. Select 
patients for therapy based on an FDA-approved companion diagnostic 
for RUBRACA.'' On April 6, 2018, the Agency approved a revised 
indication that, among other things, clarified the indication by 
listing the following specific advanced ovarian cancers in the 
indication: epithelial ovarian, fallopian tube, and primary 
peritoneal cancer.
    \2\ The study, under its abbreviated title ``ARIEL4: A Study of 
Rucaparib Versus Chemotherapy BRCA Mutant Ovarian, Fallopian Tube, 
or Primary Peritoneal Cancer Patients,'' is available on the 
National Institutes of Health (NIH) National Library of Medicine's 
ClinicalTrials.gov web page at https://clinicaltrials.gov/ct2/show/NCT02855944.
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B. Withdrawal of Approval of Indication for RUBRACA Tablets

    Therefore, under Sec.  314.150(d), approval of the indication for 
the treatment of adult patients with deleterious BRCA mutation-
associated epithelial ovarian, fallopian tube or primary peritoneal 
cancer who have been treated with two or more chemotherapies for 
RUBRACA (rucaparib) Tablets is withdrawn as of March 26, 2024. 
Withdrawal of approval of this indication does not affect any other 
approved indication for RUBRACA (rucaparib) Tablets.

II. LYNPARZA (Olaparib) Tablets

A. Application Background

    On August 17, 2017, FDA approved NDA 208558 for LYNPARZA (olaparib) 
Tablets, 100 mg and 150 mg, for the treatment of adult patients with 
advanced ovarian cancer (see table for full indication). On July 14, 
2022, FDA met with AZ to discuss the final OS results from the clinical 
trial entitled ``A Phase III, Open Label, Randomised, Controlled, 
Multi-centre Study to Assess the Efficacy and Safety of Olaparib 
Monotherapy Versus Physician's Choice Single Agent Chemotherapy in the 
Treatment of Platinum Sensitive Relapsed Ovarian Cancer in Patients 
Carrying Germline BRCA1/2 Mutations'' (SOLO3).\3\ The results indicated 
that patients who were taking olaparib potentially had a shorter OS 
than patients not on olaparib, particularly in the subgroup analysis of 
patients who had received three or more lines of chemotherapy. On July 
26, 2022, the Agency asked AZ, in writing, to

[[Page 20984]]

voluntarily permit FDA to withdraw approval of the indication for the 
treatment of adult patients with deleterious germline BRCA mutation-
associated advanced ovarian cancer who have been treated with three or 
more chemotherapies, pursuant to Sec.  314.150(d) and waive its 
opportunity for a hearing for NDA 208558. On August 19, 2022, AZ 
submitted a letter requesting withdrawal of approval of this indication 
for LYNPARZA (olaparib) Tablets (NDA 208558) pursuant to Sec.  
314.150(d) and waiving its opportunity for a hearing.
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    \3\ The study, under its abbreviated title ``Olaparib Treatment 
in Relapsed Germline Breast Cancer Susceptibility Gene (BRCA) 
Mutated Ovarian Cancer Patients Who Have Progressed at Least 6 
Months After Last Platinum Treatment and Have Received at Least 2 
Prior Platinum Treatments (SOLO3),'' is available on the NIH 
National Library of Medicine's ClinicalTrials.gov web page at 
https://clinicaltrials.gov/ct2/show/NCT02282020.
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B. Withdrawal of Approval of Indication for Lynparza Tablets

    Therefore, under Sec.  314.150(d), approval of the indication for 
the treatment of adult patients with deleterious germline BRCA 
mutation-associated advanced ovarian cancer who have been treated with 
three or more chemotherapies for LYNPARZA (olaparib) Tablets is 
withdrawn as of March 26, 2024. Withdrawal of approval of this 
indication does not affect any other approved indication for LYNPARZA 
(200laparib) Tablets.

III. ZEJULA (Niraparib) Capsules

A. Application Background

    On October 23, 2019, FDA approved NDA 208447 for ZEJULA (niraparib) 
Capsules, EQ 100 mg base, for the treatment of adult patients with 
advanced ovarian cancer (see table for full indication). On August 4, 
2022, FDA met with GSK to discuss the status of the ZEJULA (niraparib) 
Capsules indication for the treatment of adult patients with advanced 
ovarian cancer. FDA requested that GSK voluntarily permit FDA to 
withdraw approval of this indication because the results from 
randomized trials of rucaparib and olaparib in similar treatment 
settings showed OS may be reduced in patients receiving PARP 
inhibitors. FDA stated that these results from two independent trials 
were concerning and suggested a class-wide effect for PARP inhibitors. 
In correspondence dated August 24, 2022, GSK acknowledged that because 
of the uncontrolled nature of the trial entitled ``A Phase 2, Open-
Label, Single-Arm Study to Evaluate the Safety and Efficacy of 
Niraparib in Patients With Advanced, Relapsed, High-Grade Serous 
Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who 
Have Received Three or Four Previous Chemotherapy Regimens'' \4\ on 
which approval of this indication was based, it would be difficult to 
demonstrate that niraparib does not impact survival in this treatment 
setting. Therefore, GSK agreed to voluntarily withdraw the advanced 
ovarian cancer indication. On September 7, 2022, GSK submitted a letter 
requesting withdrawal of approval of this indication for ZEJULA 
(niraparib) Capsules pursuant to Sec.  314.150(d) and waiving its 
opportunity for a hearing.
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    \4\ The study, under its abbreviated title ``A Study of 
Niraparib in Patients With Ovarian Cancer Who Have Received Three or 
Four Previous Chemotherapy Regimens (QUADRA),'' is available on the 
NIH National Library of Medicine's ClinicalTrials.gov web page at 
https://clinicaltrials.gov/ct2/show/NCT02354586.
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B. Withdrawal of Approval of Indication for Zejula Capsules

    Therefore, under Sec.  314.150(d), approval of the indication for 
the treatment of adult patients with advanced ovarian, fallopian tube, 
or primary peritoneal cancer who have been treated with three or more 
prior chemotherapy regimens and whose cancer is associated with HRD 
positive status defined by either a deleterious or suspected 
deleterious BRCA mutation or genomic instability and who have 
progressed more than 6 months after response to the last platinum-based 
chemotherapy for ZEJULA (niraparib) Capsules is withdrawn as of March 
26, 2024. Withdrawal of approval of this indication does not affect any 
other approved indication for ZEJULA (niraparib) Capsules.

    Dated: March 19, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-06299 Filed 3-25-24; 8:45 am]
BILLING CODE 4164-01-P