U.S. FDA Drug Approvals for Gynecological Malignancies - A Decade in Review

Abstract

Over the last decade there has been tremendous progress in the treatment of patients with gynecologic cancers (GC) with a changing therapy landscape. This summary provides an overview of U.S. Food and Drug Administration (FDA) approvals for GC from 2010-2020, totaling 17 new indications. For each of the approved indications, endpoints, trial design, results, and regulatory considerations are outlined. Among these 17 indications, six received accelerated approval (AA) and 11 received regular approval (RA). As of September 2021, of the six AA, three have subsequently demonstrated clinical benefit resulting in conversion to RA and the remaining three have ongoing clinical trials that have not yet reported results. Approval decisions for these 17 indications were supported by primary efficacy endpoints of progression free survival (n=10), objective response rate (n=6) and overall survival (n=1) and showed a favorable benefit-risk profile. Among the 17 indications, 15 received priority review and three applications participated in one or more novel Oncology Center of Excellence initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. Current FDA thinking on drug development opportunities and regulatory initiatives currently underway will be discussed.

INTRODUCTION

The U.S. Food and Drug Administration (FDA) approval of an indication for a New Drug Application (NDA) or a Biologics Licensing Application (BLA) involves a structured framework that analyzes the target condition, critically evaluates safety and effectiveness evidence based on adequate and well-controlled studies, assesses benefits and risks from clinical data, and manages risks.¹ Two types of FDA approvals exist for NDAs and BLAs: regular approval (RA) and accelerated approval (AA). RA of an NDA or BLA requires demonstration of effectiveness based on improvement in an established endpoint for clinical benefit, whereas AA provides an alternative approval pathway for drugs or biologics treating serious or life-threatening conditions based on an earlier endpoint reasonably likely to predict clinical benefit above that of available therapies.² Following AA, additional studies may be required to confirm clinical benefit, and failure to perform confirmatory trial(s) with due diligence or failure to confirm clinical benefit may lead to withdrawal of the indication.³ With the help of other expedited drug approval programs, such as fast track designation, breakthrough therapy designation, priority review and novel initiatives established under the Oncology Center of Excellence (OCE) including the Real Time Oncology Review (RTOR), Assessment Aid (AAid), and Project Orbis, the FDA has made great strides in expediting the approval of transformative treatments for patients with cancer.^4,5,6,7 In this two-part review series, we will describe the basis for FDA approvals of treatments for gynecological (part 1) and breast (part 2) malignancies approved by the Office of Oncologic Diseases between January 1, 2010 and December 31, 2020 and discuss the relevant clinical trials, endpoints, and regulatory consideration.

DRUG APPROVALS IN GYNECOLOGIC CANCERS

Gynecologic cancers (GCs) begin in the female reproductive organs and include cervical, ovarian, uterine/endometrial, vaginal, vulvar, and fallopian tube malignancies. Depending on the location, GCs exhibit different signs, symptoms, risk factors, prognosis, disease burden, and genetic alterations.⁸ In 2021, approximately 116,760 new cases will be diagnosed and 34,080 women will die from GCs in the U.S.⁹ The incidence rate of GCs varies by cancer type and race/ethnicity.¹⁰ Over the last decade, the management of certain GCs has undergone a major transformation, owing to the better understanding of the tumor biology and immunology of the respective diseases.

Cervical Cancer

Cervical cancer (CC) is the fourth most common cancer in women worldwide, with 85% of cases occurring in developing countries.¹¹ Currently, over 293,000 women are living with CC in the U.S., and approximately 14,480 new cases will be diagnosed in 2021.¹² Persistent infection with human papilloma virus (HPV) is the most important factor in CC development and immunization to protect against the common types of HPV infection prevent specific HPV cancers in women.^13,14,15,16 In the U.S., nearly half of patients diagnosed with CC present with localized disease and the 5-year survival rate for these patients is around 90%.^12,16 In contrast, the prognosis of patients with CC that has metastasized to, or recurred at, sites not amenable to treatment by surgery or radiation is poor, with a 5-year survival rate of only 17%.¹² For the vast majority of patients diagnosed with recurrent or metastatic CC, platinum-based chemotherapy regimens are the first-line standard of care.¹⁷ Drugs approved for CC between 2010-2020 include (descriptions below provide the rationale at the time of approval; see Table 1 for summary of results):

Table 1:

Approvals in Cervical and Endometrial Cancer: 2010-2020^*

Drug (Date of Approval)	Study Design	Efficacy Population	Primary Endpoint	Select Secondary Endpoints	Approved Indication	Co-approved Companion Diagnostic Device (Device Sponsor)
Cervical Cancer
Bevacizumab18,19 (RA August 14, 2014)	GOG-0240: R, chemotherapy (paclitaxel, cisplatin and topotecan; n=225) or chemotherapy+ bevacizumab (n=227)	452 patients with persistent, recurrent, or metastatic CC	OS: median 16.8 months versus 12.9 months (HR 0.74; 95% CI: 0.58-0.94) for chemotherapy + bevacizumab versus chemotherapy	ORR: 45% (95% CI: 39-52) versus 34% (95% CI: 28-40) for chemotherapy + bevacizumab versus chemotherapy	Bevacizumab, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer	N/A
Pembrolizumab20,21 (AA June 12, 2018)	KEYNOTE-158, Cohort E: SA, OL	77 patients with tumors expressing PD-L1 (CPS ≥ 1) and received at least one line of chemotherapy in the metastatic setting	ORR: 14.3% (95% CI:7.4-24.1%) 2.6% CR and 11.7% PR DOR: NR (4.1, 18.6+ months)	N/A	Patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test	PD-L1 IHC 22C3 pharmDx (Dako North America, Inc.)
Endometrial Cancer
Pembrolizumab + Lenvatinib20,27,28,29,30,31 (AA September 17, 2019; converted to RA July 21, 2021) Utilized RTOR, Assessment Aid and Project Orbis.	Study E7080-A001-111/KEYNOTE-146: SA	94 patients with metastatic EC that were not MSI-H/dMMR and had progressed following at least one prior systemic therapy	ORR: 38.3% (95% CI: 28.5-48.9) 10.6% CR and 27.7% PR DOR: NR (1.2+ to 33.1+ months)	N/A	Patients with advanced EC that is not MSI-H or dMMR and have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.	Postmarketing commitments for an immunohistochemistry-based and a molecular-based companion diagnostic device were issued and are currently pending
	Study 309/KEYNOTE-775: OL, DB, R (1:1). Active control: investigator’s choice of doxorubicin or paclitaxel	697 non dMMR patients with advanced EC previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including neoadjuvant and adjuvant treatments	OS: 17.4 vs 12 months (HR 0.68; 95% CI: 0.56, 0.84) for pembrolizumab versus control PFS: 6.6 vs 3.8 months (HR 0.60; 95% CI: 0.50, 0.72) for pembrolizumab versus control	ORR: 30% vs 15% for pembrolizumab versus control DOR:9.2 vs 5.7 months for pembrolizumab versus control	Patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation	Postmarketing commitments from AA are still pending at this time
Tissue Agnostic
Pembrolizumab (AA May 23, 2017)20	Pembrolizumab (KEYNOTE-012, 028, 016, 158, and 164): SA	149 patients (n=14 for EC patients) with MSI-H or dMMR cancers	ORR: 36% among 14 patients with EC (95% CI:13-65) DoR: 4.2+ to 17.3+ months	N/A	Patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options	Postmarketing commitments for an immunohistochemistry-based and a molecular-based companion diagnostic device were issued and are currently pending
Pembrolizumab (AA June 16, 2020)20	KEYNOTE-158, 10 Cohorts: SA	102 patients (n=16 for CC; n=15 for EC) with various previously treated unresectable or metastatic TMB-H solid tumors	CC: ORR: 31% (95% CI:11-59) DoR: 3.7+ to 34.8+ months EC: ORR: 47% (95% CI:21-73) DoR: 8.4+ to 33.9+ months	N/A	Patients with unresectable or metastatic tumor mutational burden-high (TMB-H; ≥10 mutations/megabase) solid tumors, that have progressed following prior treatment and who have no satisfactory alternative treatment options	FoundationOne CDx assay (Foundation Medicine Inc.)

^*Data in the table reflects updated information from the recent product USPI, as dated in the references

R: Randomized; SA: Single-Arm; OL: Open-label; DB: Double-blind; PC: Placebo controlled; NR: Not Reached; TPC: Treatment of Physicians Choice; E+E: everolimus in combination with exemestane; P+E: Placebo in combination with exemestane

• Bevacizumab^18,19: In 2014, the FDA granted RA to bevacizumab in combination with paclitaxel with either cisplatin or topotecan, for the treatment of patients with persistent, recurrent, or metastatic CC. Bevacizumab was evaluated in study GOG-0240, which randomized women to receive either chemotherapy (paclitaxel, cisplatin and topotecan) or chemotherapy plus bevacizumab. The study results demonstrated improvement in OS in favor of the chemotherapy plus bevacizumab arm.

• Pembrolizumab^20,21: In 2018, the FDA granted AA to pembrolizumab for patients with recurrent or metastatic CC with disease progression on or after chemotherapy whose tumors express PD-L1 (combined positive score (CPS) ≥1). This approval was based on data from a cohort of patients with PD-L1-positive tumors with a CPS ≥1 who had received at least one line of systemic chemotherapy for metastatic disease. The trial demonstrated ORR and median duration of response (DoR) that was better than available therapies. No responses were observed in patients whose tumors did not have PD-L1 expression (CPS <1). The AA was accompanied with a post marketing requirement (PMR) for a confirmatory trial (KN-826 pembrolizumab in combination with chemotherapy in the first line setting) which has recently reported an improvement in OS.²²

Endometrial Cancer

Endometrial cancer (EC) is the most common GC in the U.S. In 2021, approximately 66,570 new cases will be diagnosed in the U.S., and 12,940 women will die from EC.²³ Recently, the diagnoses of EC have been rising worldwide with age-adjusted rate increasing on average 0.8% each year over 2008–2017.²⁴ In the U.S., the majority of ECs are diagnosed at a local stage, with 5-year survival rates of over 95%. However, for women initially diagnosed with metastatic disease, 5-year survival rates are as low as 9%.²³ Growing understanding of genetic alterations caused by DNA mismatch repair deficiencies (dMMR) or presence of microsatellite instability (MSI-H) has been actively explored to guide drug development in EC. Nearly 30% of endometrial tumors present with increased numbers of somatic mutations attributable to deficiencies in MMR and express a large number of neoantigens, potentially rendering them more susceptible to immunotherapy.^25,26 Understanding the mutational profile has now become critical in guiding treatment for advanced and recurrent EC. Drugs approved for EC between 2010-2020 include (descriptions below provide the rationale at the time of approval; see Table 1 for summary of results):

• Pembrolizumab in combination with lenvatinib ^20,27,28,29: In 2019, pembrolizumab in combination with lenvatinib received AA for the treatment of patients with advanced EC that is not MSI-H/dMMR and have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. Approval was based on Study E7080-A001-111/KEYNOTE-146, a single-arm trial that enrolled patients with metastatic EC that were not MSI-H/dMMR and had progressed following at least one prior systemic therapy. The trial demonstrated a durable ORR that was better than available therapies.²⁹ Because of the single-arm trial design, the treatment effect of each component could not be isolated. Therefore, data from previously conducted monotherapy clinical trials for lenvatinib and pembrolizumab provided supportive information for estimating the isolation of treatment effect for each agent. This marked the first approval under Project Orbis, an initiative of the FDA OCE, providing a framework for concurrent submission and review of oncology products among international partners.⁷ Data from confirmatory trial KEYNOTE-775/Study 309 showed an improvement in OS and supported conversion of this indication to RA in 2021.^30,31

Relevant Tissue Agnostic Approvals

• Pembrolizumab^20,32: In 2017, pembrolizumab received AA for patients with unresectable or metastatic, MSI-H/dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. This was the FDA’s first tissue/site-agnostic approval, based on an understanding of the biology of MSI-H/dMMR across different tumors types, including EC. A notable ORR and median DoR was observed among 14 patients with EC.³²

In 2020, pembrolizumab was granted AA for the treatment of patients with unresectable or metastatic tumor mutational burden-high (TMB-H; ≥10 mutations/megabase) solid tumors, that have progressed following prior treatment and who have no satisfactory alternative treatment options.²⁰ Approval was based on prospectively planned retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors enrolled in KEYNOTE-158 including patients with CC and EC. Patients with CC and EC demonstrated a notable ORR and median DoR.^20,33

In April 2021, dostarlimab also received AA for the treatment of adult patients with dMMR recurrent or advanced EC, that has progressed on or following prior treatment with a platinum-containing regimen.³⁴ In August 2021, the indication was expanded to include dMMR solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.³⁴ These approvals highlight the biomarker directed drug development and provide treatment option for patients with MSI-H or TMB-H malignancies who experience disease progression or recurrence after initial systemic therapy.

Ovarian Cancer

Ovarian cancer (OC) ranks as the fifth leading cause of cancer death in women and estimates for 2021 suggest that 21,410 new cases will be diagnosed and 13,770 women will die from OC in the U.S.³⁵ Nearly 75% of patients present with advanced disease at initial diagnosis, with a 5-year survival rate of 30%.^36,37 The emergence of targeted therapies, such as poly (ADP-ribose) polymerase inhibitors (PARPi), has offered promising new treatment options for patients with OC by targeting tumors with homologous recombination repair pathway deficiencies (HRD). Since 2010, there have been 12 new FDA-approved indications for OC, of which nine are for PARPi (Table 2) and three for bevacizumab-containing regimens for treatment of first-line and recurrent disease (both platinum resistant and sensitive; Table 3). Drugs approved for epithelial ovarian, fallopian tube, or primary peritoneal cancer (henceforth referred as OC) between 2010-2020 include (descriptions below provide the rationale at the time of approval):

Table 2:

Poly (ADP-Ribose) Polymerase (PARP) Inhibitor Approvals in Ovarian Cancer: 2010-2020^*

Drug (Date of Approval)	Study Design	Efficacy Population	Primary Endpoint	Select Secondary Endpoints	Approved Indication	Co-approved Companion Diagnostic Device (Device Sponsor)
First-Line maintenance
Olaparib41,55,56 (RA December 19, 2018) Utilized Assessment Aid	SOLO-1: R (2:1), DB, olaparib versus placebo	391 patients with BRCAm newly diagnosed advanced OC	PFS: NR versus 13.8 months (HR: 0.30; 95% CI: 0.23, 0.41) for BRCAm population versus placebo	OS: Not mature	Patients with BRCA-mutated (BRCAm) advanced ovarian, fallopian tube, or primary peritoneal cancer who had responded after first-line platinum-based chemotherapy.	Two companion diagnostic tests are approved with this indication: 1. BRACAnalysis CDx, for germline BRCA1/2 alterations (Myriad Genetic Laboratories, Inc.) 2. FoundationOne CDx, for BRCA1/2 alterations (Foundation Medicine, Inc.)
Niraparib50,57 (RA April 29, 2020)	PRIMA: R (2:1), DB, niraparib versus placebo	733 patients in complete or partial response to first-line platinum-based chemotherapy	PFS: 21.9 (95% CI: 19.3-NE) versus 10.4 (95% CI:8.1-12.1) months (HR 0.43; 95% CI: 0.31-0.59) for niraparib versus placebo in the HRD population PFS: 13.8 (95% CI: 11.5-14.9) versus 8.2 (95% CI:7.3-8.5) months (HR 0.62; 95% CI: 0.50-0.76) for niraparib versus placebo in the overall population	OS: Not mature	Patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.	Myriad myChoice CDx (Myriad Genetic Laboratories, Inc.)
Olaparib + Bevacizumab18,41,55,58 (RA May 8, 2020) Utilized Assessment Aid	PAOLA-1: R (2:1), DB, O+B versus P+B	806 patients with newly diagnosed advanced OC	PFS: 37.2 vs 17.7 months (HR 0.33; 95% CI: 0.25–0.45) for O+B versus P+B in HRD-positive population	OS: Not mature	Patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: • a deleterious or suspected deleterious BRCA mutation, and/or • genomic instability	Complementary Diagnostic: aMyriad myChoice CDx (Myriad Genetic Laboratories, Inc.)
Recurrent maintenance
Niraparib50,51,52 (RA March 27, 2017)	NOVA: R (2:1), DB, niraparib versus placebo	553 patients with platinum-sensitive recurrent OC	PFS: 21.0 (95% CI: 12.9-NR) versus 5.5 (95% CI: 3.8-7.2) months (HR 0.43; 95% CI: 0.17-0.41) for niraparib versus placebo in the gBRCA cohort PFS: 9.3 (95% CI: 7.2 – 11.2) versus 3.9 (95% CI: 3.7 – 5.5) months (HR 0.45; 95% CI: 0.34 – 0.61) for niraparib versus placebo in the non-gBRCA cohort	OS: Not mature	Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.	BRACAnalysis CDx (Myriad Genetic Laboratories, Inc.)
Olaparib41,44 (RA August 17, 2017)	SOLO-2: R (2:1), DB, olaparib versus placebo	295 patients with gBRCAm OC	PFS: 19.1 versus 5.5 months (HR 0.30; 95% CI: 0.54–1) for olaparib versus placebo	OS: 51.7 versus 38.8 months (HR 0.74; 95% CI: 0.22–0.41) for olaparib versus placebo	Patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.	N/A
	Study 19: R (1:1), DB, olaparib versus placebo	265 patients with platinum-sensitive OC who had received 2 or more previous platinum-containing regimens	PFS: 8.4 versus 4.8 months (HR 0.35; 95% CI: 0.25–0.49) for olaparib versus placebo	OS: 29.8 versus 27.8 months (HR 0.73; 95% CI: 0.55–0.95) for olaparib versus placebo
Rucaparib46,49 (RA April 6, 2018)	ARIEL-3: R (2:1), DB, rucaparib versus placebo	564 patients with recurrent OC who were in response to platinum-based chemotherapy	PFS: 10.8 vs 5.4 months (HR 0.36; 95% CI: 0.30–0.45) for rucaparib versus placebo in all patients PFS: 13.6 vs 5.4 months (HR 0.32; 95% CI: 0.24–0.42) rucaparib versus placebo in HRD group PFS: 16.6 vs 5.4 months (HR 0.23; 95% CI: 0.16–0.34) for rucaparib versus placebo in tBRCA group	OS: Not mature	Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy	b,cFoundationFocus CDxBRCA LOH (Foundation Medicine, Inc.)
Third-line and beyond treatment
Rucaparib46,47 (AA December 19, 2016; converted to RA April 6, 2018)	ARIEL-2 and Study 10: SA, OL	106 patients with advanced BRCAm OC [Study 10 (n=42); ARIEL-2 (n=64)]	ORR: 54% (95% CI: 44-64) Median DoR of 9.2 months (95% CI: 6.6-11.6)	N/A	Patients with a deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies.	FoundationFocus CDxBRCA test (Foundation Medicine Inc.)
Fourth-line and beyond treatment
Olaparib41,42,43 (AA December 19, 2014; converted to RA August 17, 2017)	Study 42: SA	137 gBRCAm patients with measurable disease at baseline and had received three or more prior lines of chemotherapy	ORR: 34% (95% CI:26–42) Median DOR of 7.9 (95% CI: 5.6-9.6) months	N/A	Patients with deleterious or suspected deleterious germline BRCA mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.	The BRACAnalysis CDx (Myriad Genetic Laboratories, Inc.)
Niraparib50,53 (RA October 23, 2019)	QUADRA: SA	98 patients with advanced OC with HRD positive tumors who have been treated with 3 or more prior lines of chemotherapy; HRD+ status was classified as either tBRCAm (n=63) and/or a genomic instability score (GIS) ≥ 42 (n=35)	ORR: 24% (95% CI:16-34) in HRD+ cohort Median DoR of 8.3 months (95% CI: 6.5 -NE) in HRD+ cohort ORR: 39% (95% CI:17-64) in patients with tBRCAm OC, platinum-sensitive disease ORR: 29% (95% CI:11-52) in patients with tBRCAm OC, platinum-resistant disease ORR: 19% (95% CI:4-46) in patients with tBRCAm OC, platinum-refractory disease		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 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 six months after response to the last platinum-based chemotherapy	Myriad myChoice CDx test (Myriad Genetic Laboratories, Inc.)

^*Data in the table reflects updated information from the recent product USPI, as dated in the references

O+B: Olaparib + bevacizumab maintenance; P+B: Placebo + bevacizumab maintenance

^aMyriad myChoice CDx was co-approved to demonstrate benefit/risk assessment of the drug (specifically, to demonstrate enhanced progression-free survival (PFS) from Zejula (niraparib) maintenance therapy in accordance with the Zejula product label)

^bFoundationFocus CDx_{BRCA LOH} was co-approved to demonstrate benefit/risk assessment of the drug (specifically, to demonstrate improved progression-free survival (PFS) from Rubraca (rucaparib) maintenance therapy in accordance with the RUBRACA product label)

^cThe reporting of FoundationFocus CDx_{BRCA LOH} HRD status (defined as tBRCA-positive and/or LOH high) in ovarian cancer patients was discontinued and approved under F1CDxin April 2019

Table 3:

Bevacizumab Approvals in Ovarian Cancer: 2010-2020^*

Trial supporting approval	Population Studied	Study Design	Primary Endpoint	Select Secondary Endpoints	Approved Indication
GOG-021818	First-Line OC treatment and maintenance	DB, PC, R (1:1:1) CPB+B (n=623) versus CPB (n=625) versus CP (n=625)	PFS: median 18.2 versus 12 months (HR 0.62; 95% CI: 0.52–0.75) for CPB+B versus CP	OS: median 43.8 versus 40.6 months (HR 0.89; 95% CI: 0.76–1.05) for CPB+B versus CP	Patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with carboplatin and paclitaxel, followed by single-agent bevacizumab, for stage III or IV disease after initial surgical resection. RA granted on June 13, 2018
PAOLA-118,41,55,57	First-Line maintenance	DB, PC, R (2:1) O+B (n=537) versus P+B (n=269)	PFS (HRD-positive population): median 37.2 versus 17.7 months (HR 0.33; 95% CI: 0.25-0.45)	OS: Immature	In combination with olaparib for patients with newly diagnosed advanced ovarian cancer associated with homologous recombination deficiency positive (HRD+) status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. RA granted on May 8, 2020
OCEANS18,39	Recurrent OC, platinum sensitive	R (1:1) CG+B (n=242) versus CG+P (n=242)	PFS: median 12.4 versus 8.4 months (HR 0.46; 95% CI: 0.37, 0.58)	OS: Not significantly improved (HR 0.95; 95% CI: 0.77 - 1.17) ORR: 78% versus 57%	In combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine chemotherapy, followed by bevacizumab alone, for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. RA granted on December 6, 2016
GOG-021318,40		R (1:1) CPB (n=337) versus CP (n=336)	OS: median 42.6 versus 37.3 months (HR 0.82; 95% CI: 0.68, 0.996)	PFS: median 13.8 versus 10.4 months (HR 0.61; 95% CI: 0.51, 0.72) for CPB versus CP ORR: 78% versus 56%
AURELIA18,38	Recurrent OC, platinum resistant	R (1:1) Chemo + Bevacizumab (n=179) versus Chemo (n=182)	PFS: median 6.8 versus 3.4 months (HR 0.38; 95% CI: 0.30–0.49)	OS: median 16.6 versus 13.3 months (HR 0.89; 95% CI: 0.69–1.14) ORR: 28% versus 13% DoR: 9.4 versus 5.4 months	In combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for the treatment of patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. RA granted on November 14, 2017

^*Data in the table reflects updated information from the recent product USPI, as dated in the references

R: Randomized; DB: Double-blind; PC: Placebo controlled; CP: carboplatin plus paclitaxel; CPB: carboplatin plus paclitaxel with bevacizumab; CPB+B: carboplatin plus paclitaxel with bevacizumab for six cycles followed by single-agent bevacizumab maintenance treatment; O+B: olaparib

⁺bevacizumab maintenance; P+B: placebo + bevacizumab maintenance; CG+B: carboplatin plus gemcitabine with bevacizumab; CG+P: carboplatin plus gemcitabine with placebo; Chemo: weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin

Approvals in Recurrent Ovarian Cancer (ROC) – Treatment and Maintenance:

• Bevacizumab^18,38: In 2014, the FDA approved bevacizumab in combination with paclitaxel, pegylated-liposomal doxorubicin, or topotecan for the treatment of patients with platinum-resistant ROC. RA was based on the results from AURELIA, a randomized trial, which evaluated bevacizumab plus chemotherapy (weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin) versus chemotherapy in patients with platinum-resistant ROC. This trial demonstrated a statistically significant improvement in PFS in the bevacizumab arm. While no significant difference in OS was observed, exploratory analyses in the paclitaxel plus bevacizumab group showed a more favorable OS.

  In 2016, the FDA approved bevacizumab either in combination with carboplatin and paclitaxel (CP) or with carboplatin and gemcitabine (CG), followed by bevacizumab alone, for the treatment of patients with platinum-sensitive ROC. Efficacy was demonstrated in two trials OCEANS and GOG-213.^39,40 OCEANS randomized patients to CG and bevacizumab (CG+B) versus CG and placebo (CG+P) and demonstrated a PFS improvement (OS was not significantly improved) with addition of bevacizumab. The second trial, GOG-0213 randomized patients to either CP and bevacizumab (CPB) or CP and showed an improvement in OS and PFS on the CPB arm compared to the CP arm. The totality of evidence from these two trials served as the basis for granting bevacizumab this indication.

• Olaparib⁴¹: In 2014, the FDA granted AA to the first PARPi, olaparib, for the treatment of patients with gBRCAm advanced OC who have been treated with three or more prior lines of chemotherapy. Approval was based on a cohort of patients with gBRCAm OC who had measurable disease at baseline and had received three or more prior lines of chemotherapy. A clinically meaningful confirmed ORR and median DoR formed the basis of this approval that was better than available therapies. With this approval, olaparib became the first new molecular entity to be approved for the treatment of ovarian cancer since 1996. Data from SOLO-2 verified the clinical benefit and supported conversion of this indication to RA in 2017.^42,43

  Olaparib received RA in 2017 for use as maintenance treatment of patients with ROC, in CR or PR to platinum-based chemotherapy. This approval was based on SOLO-2 and Study 19. SOLO-2 randomized patients with gBRCAm, relapsed, platinum-sensitive OC to olaparib versus placebo and olaparib arm showed a statistically significant and large magnitude of improvement in PFS.⁴⁴ Data from Study 19, which randomized patients to olaparib versus placebo without regard for BRCA status, demonstrated an improvement in PFS for patients randomized to olaparib in the intention-to-treat (ITT) platinum-sensitive population, exploratory analyses showed benefit in the gBRCA wild type population, longer follow up demonstrated acceptable safety and long term benefit including for patients with gBRCA wild type status, and thus the totality of evidence supported approval in a broader indication.⁴⁵

• Rucaparib⁴⁶: In 2016, the FDA granted AA to rucaparib for treatment of patients with BRCAm advanced OC who have been treated with two or more chemotherapies. Approval was based on data from two single-arm trials, ARIEL-2 and Study 10.⁴⁷ The efficacy population demonstrated a clinically meaningful ORR and median DoR.⁴⁸ This AA was accompanied with a PMR to verify and describe the clinical benefit.

  In 2018, rucaparib received FDA approval for maintenance treatment of ROC who are in a CR or PR after platinum-based chemotherapy. Approval was based on ARIEL-3 with analysis of PFS performed in 3 cohorts - tBRCAm; HRD which included tBRCAm and loss of heterozygosity (LOH); and the ITT population, which included tBRCAm, LOH, and biomarker negative.⁴⁹ ARIEL-3 demonstrated a statistically and clinically significant improvement in PFS for patients randomized to rucaparib in the tBRCAm population, the HRD population, and the ITT population. This data from ARIEL-3 also served to support the conversion of the previous AA of rucaparib to RA in 2018.

• Niraparib⁵⁰: In 2017, FDA approved niraparib for maintenance treatment of patients with ROC in response to platinum-based chemotherapy. RA was based on NOVA, which randomized patients to niraparib versus placebo in two separate cohorts - gBRCAm and non-gBRCAm.⁵¹ Improvement in PFS was observed in both the gBRCAm and the non-gBRCAm cohorts, for niraparib compared to placebo.⁵² Prior to this approval, bevacizumab was the only approved maintenance option and this indication provided a PARPi as a maintenance treatment option for patients with ROC who are in response to platinum-based chemotherapy, regardless of BRCA status.

  In 2019, niraparib received RA for treatment of patients with advanced OC treated with three or more prior chemotherapy regimens and whose cancer is associated with HRD-positive (HRD+) status (defined by either a BRCAm mutation, or genomic instability, in patients with disease progression greater than six months after response to the last platinum-based chemotherapy). The approval was based on efficacy data from patients with advanced OC with HRD+ tumors in single-arm QUADRA trial.⁵³ HRD+ status was classified as either tBRCAm and/or a genomic instability score (GIS) ≥ 42. The study demonstrated a clinically meaningful ORR and median DoR in this patient population. Additionally, because niraparib had already received RA in the earlier maintenance setting, this approval based upon QUADRA was also granted a RA, since further confirmation of the benefit was not required.

Approvals in First Line OC – Treatment and Maintenance:

• Bevacizumab¹⁸: In 2018, the FDA approved bevacizumab for patients with OC in combination with carboplatin and paclitaxel, followed by bevacizumab as a single agent, for stage III or IV disease after initial surgical resection. Approval was based on GOG-0218, which randomized patients to carboplatin plus paclitaxel, carboplatin plus paclitaxel with bevacizumab, or carboplatin plus paclitaxel with bevacizumab for six cycles followed by maintenance bevacizumab.⁵⁴ The study demonstrated improvement in PFS with addition of bevacizumab. Data from ICON-7 trial (which enrolled a slightly different study population and dose of bevacizumab) provided additional supportive information for granting this indication.

• Olaparib⁴¹: In 2018, olaparib was approved as maintenance treatment for patients with newly diagnosed BRCAm advanced OC. Approval was based on SOLO-1, which randomized BRCAm patients to receive olaparib or placebo.^55,56 SOLO-1 demonstrated a statistically significant improvement in PFS with median PFS not reached in the olaparib arm. Although the trial primarily included gBRCAm patients, given the biologic rationale that an underlying BRCAm (germline or somatic), results in HRD and confers sensitivity to PARPi, the indication was granted for patients with both germline and somatic BRCAm. With this approval, the FDA approved the first PARP inhibitor for the first-line maintenance treatment of women with advanced OC following cytoreductive surgery and chemotherapy. This represented a major change to the standard of care for adult patients with BRCAm tumors undergoing initial therapy for OC.

• Niraparib⁵⁰: In 2020, niraparib was granted approval for the maintenance treatment of patients with advanced OC who are in CR or PR to first-line platinum-based chemotherapy. Approval was based on PRIMA, which randomized patients to either niraparib or placebo.⁵⁷ Tumor samples were tested for presence of tumor BRCAm (tBRCAm) or genomic instability score (GIS)≥42, which defined the HRD+ population. In the HRD+ and overall population, trial demonstrated improvement in PFS with addition of niraparib. An additional aspect of this trial was approval of a modified dosing regimen (300mg versus 200mg) for patients based on body weight ≥ 77 kg and with baseline platelet count ≥ 150,000/μL. PRIMA was not prospectively designed to assess the difference between the starting doses with respect to efficacy; however, the subgroup analyses supported that efficacy is similar for patients receiving the 200mg starting dose as dictated by baseline weight or platelet count, as for those receiving the fixed 300mg starting dose in this treatment setting. The product labeling was updated to reflect the modified dosing regimen to be implemented in this therapeutic setting.

• Olaparib in combination with bevacizumab^41,18: In 2020, olaparib in combination with bevacizumab received approval as maintenance treatment for patients with newly diagnosed advanced OC associated with HRD+ status defined by either a deleterious or suspected deleterious BRCAm, and/or genomic instability. Approval was based on PAOLA-1, which randomized patients to olaparib plus bevacizumab versus placebo plus bevacizumab.^53,58 An improvement in PFS in the HRD+ subgroup was observed in the olaparib plus bevacizumab arm. PAOLA-1 included 34% HRD-negative and 18% HRD-unknown patients. No benefit of PFS and OS was observed in the HRD-negative subgroup, so the approval indication was limited to the HRD+ population.⁵⁹

DISCUSSION

After several years of slow progress in GC drug development, the last decade witnessed approvals of multiple therapeutics, altering the treatment landscape for certain GCs. Between 2010-2020, six products received FDA approvals for 17 indications, including two in CC, one in EC, twelve in OC, and two tumor agnostic indications, with great impact and relevance to GCs (Figure 1). Of the 17 indications, 11 (65%) received RA and six (35%) were granted AA. Of the six AA, three confirmed benefit (one in July 2021) and were subsequently converted to RA; the remaining three are pending verification of benefit with ongoing clinical trials. AA can thus result in approval of drugs years earlier than they would have otherwise been approved. Although some uncertainty remains with accelerated approvals, this is balanced with bringing therapies to patients with refractory tumors without satisfactory treatment options and further confirmatory data will be provided as part of postmarketing trials. Approval decisions for the 17 indications, were supported by primary efficacy endpoints of PFS in 59%, ORR in 35% and OS in 6%, showing a favorable benefit-risk profile. Use of earlier clinical endpoints such as ORR and PFS allows for a smaller sample size and a shorter duration of follow-up as compared to OS. While OS is considered the "gold-standard", it is generally not required as the primary endpoint in randomized controlled studies, given the long follow-up periods, equipoise for drugs with high response rates, and challenges with multiple therapies confounding the result. Survival data (often a secondary or co-primary endpoint) is always evaluated along with other endpoints to ensure that it is numerically favorable. ORR serves as the most common endpoint used in single arm trials as time-to-event endpoints such as PFS and OS are not interpretable in a single arm trial design. ORR is based on an objective and quantitative assessment that reflects the drug’s antitumor activity as tumor shrinkage would not be expected without intervention. Approvals that are granted based on response rate and duration as primary source of efficacy generally are approved under Accelerated Approval. Of note, among the 17 indications, 15 received priority review and three applications utilized one or more novel OCE initiatives, including RTOR, AAid, and Orbis.

Figure 1: FDA Approvals in Gynecologic Malignancies: 2010-2020^66,66.

(Figure represents indication granted at time of approval.)

With better understanding of GC immunology, immune checkpoint inhibitors (ICI) and combination regimens have significantly improved clinical outcomes for patients. Understanding regarding presence of foreign HPV epitopes, enhanced tumor immune recognition and expression of PD-L1, made CC a prime candidate for PD-1/PD-L1 inhibition and lead to an AA of pembrolizumab for the treatment of PD-L1+ advanced CC.⁶⁰ However further immunotherapy biomarker refinement is warranted to better select the patient population that will respond, and combinatorial designs are underway to further boost the activity of immunotherapy monotherapies. Use of ICI in EC has also been a growing area of interest and pembrolizumab as a single agent and in combination with lenvatinib received AA in MSI-H and not MSI-H EC, respectively. Pembrolizumab also received AA for unresectable or metastatic TMB-H solid tumors, providing another treatment option based on tumor genomic profiling. In 2021, FDA granted AA to dostarlimab for dMMR recurrent or advanced EC based on ORR. In these cases, agents were granted AA based on durable response rates considered reasonably likely to predict for clinical benefit in populations for whom no approved therapies existed. Along with benefits, these advances have also highlighted challenges, including difficulties identifying subpopulations most likely to respond to immunotherapy, determining contribution of effect in combination regimens, and enrollment of smaller biomarker subsets.

Historically, patients with advanced OC received chemotherapy and then returned to watchful waiting until progression. Enhanced understanding of tumor biology and emergence of PARPi introduced maintenance therapy options for patients with advanced OC after chemotherapy for both newly diagnosed and recurrent OC. Among the 3 PARPis, FDA granted approvals for 9 indications, expanding the OC treatment paradigm (Table 2). Of the nine indications, seven (78%) were granted RA based on magnitude of PFS improvement. As an endpoint, PFS assessment allows for shorter follow-up with smaller sample sizes and is not confounded by subsequent therapies or crossover. Additionally, PFS incorporates a direct measure of disease and is relevant for clinical practice, as tumor progression signals resistance and triggers therapy change. While a statistically significant improvement in OS was not required for these indications, OS is always analyzed along with PFS and must not be trending in a negative direction. Five of the PARPi indications were approved with a companion diagnostic deemed to be required for the safe and effective use of the drug in that setting. Platinum sensitivity, BRCAm, and platinum responsiveness remain the main predictors of HRD/PARPi benefit and resistance to PARPi remains a critical hurdle to continued treatment response. Further elucidation of PARPi resistance and response are being investigated along with combinatorial approaches, including ICIs. Overall, PARPis represent a notable advance in the treatment landscape for OC, as prior to these approvals, treatment had only minimally improved outcomes, despite efforts to modify schedules, dose-intensity and routes of delivery.^61,62,63

Despite this progress, OC patients who develop platinum-resistant and platinum-refractory disease still have limited treatment options but additional studies in this population are underway. Several novel combinations, such as PARPi in combination with immunotherapy, chemotherapy, and targeted agents, are being explored to overcome eventual resistance to PARPi and increase tumor sensitivity.

FDA conducted two public private partnership meetings in collaboration with the American Association for Cancer Research and the Society of Gynecologic Oncology during 2010-2020 to advance the development of novel therapeutics for the treatment of GC.^64,65 These workshops highlighted clinical trial design considerations, challenges, and solutions surrounding scientific advancements in GC. The workshops outlined a path forward, encouraging exploration of innovative approaches and therapeutic development to overcome resistance mechanisms and improve the efficacy of existing agents. With continued advancements in molecular biology, new potential targets would be identified that may generate novel therapeutic platforms, including those less common and high unmet medical need GC, such as vaginal and vulvar cancers, OC subtypes including clear cell, endometrioid, mucinous, and endometrial stromal sarcomas.

CONCLUSION

The progress observed in the last decade suggests FDA expedited programs have resulted in earlier drug approval of promising regimens with the use of earlier end points other than OS. As exemplified by PARPi and ICI, expedited programs such as AA helped bring novel therapies to patients with unmet needs years ahead of schedule. Currently, 495 clinical trials are recruiting women with CC, 183 for EC, and 473 for OC listed on clinicaltrials.gov in the U.S., exploring myriad interventions including antibody drug conjugates, immunotherapy, peptide vaccines and other novel combinations.⁶⁶ Using early signs of clinical benefit such as ORR and PFS has led to the approval of practice changing therapies for GC, and provided treatment options in settings where no satisfactory alternative treatment existed.