Ovarian cancer: new strategies and emerging targets for the treatment of patients with advanced disease

Figures & data

Figure 1. FDA-approved drugs in advanced ovarian cancer

dMMR: deficient mismatch repair, FDA: US Food and Drug Administration, HRD: homologous recombination deficiency, L: line of treatment, MSI: microsatellite instability high, mut: mutated, PlSOC: platinum-sensitive ovarian cancer, PlROC: platinum-resistant ovarian cancer, PLD: pegylated liposomal doxorubicin.

Table 1. Pivotal trials and FDA approvals of PARP and VEGF inhibitors in advanced ovarian cancer

Drug	Maintenance	Later-Line Treatment	FDA Approval
Olaparib^a	SOLO-2 (BRCA-mutated) Study 19 (Aug 17, 2017) SOLO-1 (BRCA-mutated) (Dec 19, 2018) PAOLA-1 (HRD-positive) (May 8, 2020)	Study 42 (BRCA-mutated) (Dec 19, 2014)	> 3^rd line, germline BRCA, treatment (Dec 19, 2014) > 2^nd line, no biomarker, maintenance after response to platinum (Aug 17, 2017) Front-line, germline and somatic BRCA, maintenance after response to platinum (Dec 19, 2018) Front-line olaparib plus bevacizumab, HRD-positive, maintenance after response to platinum (May 8, 2020)
Niraparib^b	NOVA (Mar 27, 2017) ENGOT-OV26/PRIMA (April 29, 2020)	QUADRA (Oct 23, 2019)	2^nd line, no biomarker, maintenance after response to platinum (March 27, 2017) >3^rd line, HRD+, germline and somatic BRCA, platinum-sensitive, treatment (Oct 23, 2019) Front-line maintenance after response to platinum (April 29, 2020)
Rucaparib^c	ARIEL3 (April 6, 2018)	Study 10 (BRCA-mutated) ARIEL2 (BRCA-mutated) (Dec 19, 2016)	> 2^nd line, germline and somatic BRCA, treatment (Dec 19, 2016) > 2^nd line, no biomarker, maintenance after response to platinum (Apr 6, 2018)
Bevacizumab^d	GOG218 (June 13, 2018) OCEANS – GOG213 (Dec 6, 2016)	AURELIA (Nov 14, 2014)	1^st and later-line treatment plus maintenance (Nov 14, 2014; Dec 6, 2016; June 13, 2018)

^aOlaparib Prescribing Information. AstraZeneca Pharmaceuticals LP, May 2020; ^bNiraparib Prescribing Information. Tesaro Inc., April 2020; ^cRucaparib Prescribing Information. Clovis Oncology Inc., May 2020; ^dBevacizumab Prescribing Information. Genentech/Roche, May 2020.

FDA: US Food and Drug Administration, HRD: homologous recombination deficiency, PARP: poly ADP ribose polymerase, VEGF: vascular endothelial growth factor.

Table 2. Pivotal trial results for front-line maintenance therapy in patients with newly diagnosed, advanced ovarian cancer after response to platinum-based therapy

Drug/Regimen	Phase III Trial	Patient Population	N	Outcomes	Reference
Niraparib vs placebo	ENGOT-OV26/PRIMA	ITT	733	mPFS, 13.8 v 8.2 mo, HR 0.62, p < .001; mOS at 24 mo, 84% v 77%, HR 0.70	Gonzalez-Martin et al., 2019
		HRD+ (including BRCA-mt+)	373	mPFS, 21.9 v 10.4 mo, HR 0.43, p < .001
Veliparib vs placebo	VELIA	ITT	1140	mPFS, 23.5 v 17.3 mo, HR 0.68, p < .001	Coleman et al., 2019
		HRD+ (including BRCA-mt+)	421	mPFS, 31.9 v 20.5 mo, HR 0.57, p < .001
		BRCA-mt+	200	mPFS, 34.7 v 22.0 mo, HR 0.44, p < .001
Olaparib plus bev vs placebo plus bev	PAOLA-1	ITT	806	mPFS, 22.1 v 16.6 mo, HR 0.59, p < .001	Ray-Coquard et al., 2019
		HRD+ (including BRCA-mt+)	387	mPFS, 37.2 v 17.7 mo, HR 0.33
		HRD+ (not including BRCA-mt+)	150	mPFS, 28.1 v 16.6 mo, HR 0.43
		BRCA-mt+	237	mPFS, 37.2 v 21.7 mo, HR 0.31
		HRD-negative	277	mPFS, 16.6 v 16.2 mo, HR 1.00

Bev: bevacizumab, HRD: homologous recombination deficiency, HR: hazard ratio, ITT: intent to treat, mo: month, mOS: median overall survival, mPFS: median progression-free survival.

Table 3. Single-agent treatment with PD-1/PD-L1 immune checkpoint inhibitors in patients with advanced ovarian cancer

Agent	Study Phase	Patient Population	N	Outcomes	Reference
Anti-PD-1 antibodies
Nivolumab	II	Platinum-resistant OvCa	20	ORR, 15%; durable CR in 2 patients; DCR, 45%; mPFS, 3.5 months; mOS, 20 months	Hamanishi et al., 2015
Nivolumab vs gemcitabine or pegylated liposomal doxorubicin	III (NINJA) randomized	Advanced or recurrent platinum-resistant OvCa	316	ORR, 8% v 13%; Duration of reponse: 18.7 v 7.4 months; mPFS, 2.1 v 3.8 months (HR, 1.46; p = .002); mOS: 10.1 v 12.1 months (HR, 1.03; p = .808).	Omatsu et al., 2020
Pembrolizumab	Ib	Advanced OvCa (73.1% of patients with ≥3 prior lines of therapy.	26, PD-L1+	ORR, 11.5%; mPFS, 1.9 months; mOS, 13.8 months	Varga et al., 2019
Pembrolizumab	II	Recurrent OvCa (1–3 prior lines of therapy, PFI/TFI 3–12 months)	285 (cohort A)	ORR, 7.4%; mDOR 8.2 months; DCR, 37.2%; mPFS, 2.1 months; mOS not reached	Matulonis et al., 2019
Pembrolizumab	II	Recurrent OvCa (4–6 prior lines of therapy, PFI/TFI ≥ 3 months)	91 (cohort B)	ORR, 9.9%; mDOR not reached; DCR, 37.4%; mPFS, 2.1 months; mOS 17.6 months	Matulonis et al., 2019
PF-06801591	I	Advanced OvCa	15	ORR, 20%; mPFS, 5.3 months; mOS, not reached	Johnson et al., 2019
Anti-PD-L1 antibodies
Atezolizumab	Ia	Recurrent OvCa	12	ORR, 22%; durable PR in 2 patients; mPFS, 2.9 months; mOS, 11.3 months	Infante et al., 2016; Liu et al., 2019
Avelumab	Ib	Recurrent or refractory OvCa (median 3 prior lines of therapy)	125	ORR, 9.6%; mDOR, 10.4 months; DCR, 42%; mPFS, 2.6 months; mOS, 11.2 months	Disis et al., 2019

CR: complete response, DCR: disease control rate, mDOR: median duration of response, mOS: median overall survival, mPFS: median progression-free survival, OvCa: ovarian cancer, PD-1: programmed death receptor 1, PD-L1: PD ligand 1, PFI: platinum-free interval, PR: partial response, TFI: treatment-free interval.

Table 4. Investigational combination regimens in patients with advanced ovarian cancer

Clinical Trial	CT	P	I	A	Treatment	Patient Population^a	Phase	Primary EP
Chemotherapy-based combinations (CT ± PARPi ± anti-PD-1/PD-L1 antibody ± VEGFRi)
FIRST/ENGOT-ov44 (NCT03602859)		m			Platinum-based CT + TSR-042 (dostarlimab) followed by niraparib + TSR-042 vs CT followed by niraparib maintenance vs CT	1^st line, stage III–IV OvCa	Randomized, double-blind, phase III	PFS
KEYLYNK-001/ENGOT-ov43 (NCT03740165)		m			CT (carboplatin/paclitaxel) + pembrolizumab followed by olaparib maintenance or CT (carboplatin/paclitaxel) + pembrolizumab vs CT (carboplatin/paclitaxel) (study arms may include bev)	1^st line, BRCA non-mutated OvCa	Randomized, double-blind, phase III	PFS, OS
IMagyn050/GOG 3015/ENGOT-ov39 (NCT03038100)					CT (carboplatin/paclitaxel) + atezolizumab + bev followed by maintenance atezolizumab + bev vs CT (carboplatin/paclitaxel) + bev followed by bev	Stage III–IV OvCa after tumor-reductive surgery	Randomized, double-blind, phase III	PFS, OS
DUO-O/ENGOT-ov46 (NCT03737643)		m		m	CT + durvalumab followed by maintenance durvalumab + olaparib + optional bev	Newly diagnosed OvCa, BRCA-mutated	Randomized, open-label, phase III	PFS
DUO-O/ENGOT-ov46 (NCT03737643)		m			CT + durvalumab + bev followed by maintenance durvalumab + olaparib + bev vs CT + durvalumab + bev followed by maintenance durvalumab + bev vs CT + bev followed by maintenance bev	Newly diagnosed OvCa, non BRCA-mutated	Randomized, double-blind, phase III	PFS
ATHENA/ENGOT-ov45 (NCT03522246)		m		m	Platinum-based CT followed by maintenance rucaparib + nivolumab vs rucaparib vs nivolumab vs placebo	Responders to front-line chemotherapy	Randomized, double-blind, phase III	PFS
ICON 9 (NCT03278717)		m		m	Platinum-based CT followed by maintenance olaparib + cediranib vs platinum-based CT followed by maintenance olaparib	Relapsed, platinum-sensitive OvCa (responders ≥4 cycles of CT)	Randomized, open-label, phase III	PFS, OS
ANITA/ENGOT-ov41/GEICO 69-O (NCT03598270)		m			Platinum-based CT (investigator’s choice) + atezolizumab followed by maintenance niraparib + atezolizumab vs CT (investigator’s choice) followed by maintenance niraparib	Recurrent OvCa, TFIp >6 mos	Randomized, double-blind, phase III	PFS
ATALANTE (NCT02891824)					Platinum-based CT + atezolizumab + bev ± maintenance atezolizumab + bev vs platinum-based CT + bev followed by maintenance bev	Recurrent OvCa, TFIp >6 mos	Randomized, double-blind, phase III	PFS
NRG-GY009 (NCT02839707)					Pegylated liposomal doxorubicin (PLD) + atezolizumab or PLD + atezolizumab + bevacizumab vs PLD + bevacizumab	Platinum-resistant OvCa	Randomized, open-label, phase II–III	PFS, OS
PARPi + VEGFRi combinations
NSGO-AVANOVA2/ENGOT-ov24 (NCT02354131)					Niraparib + bev vs niraparib	Relapsed, platinum-sensitive OvCa	Randomized, open-label, phase II	PFS
NRG-GY004 (NCT02446600)					Olaparib + cediranib or olaparib vs standard platinum-based CT	Relapsed, platinum-sensitive OvCa	Randomized, open-label, phase III	PFS
NRG-GY005/COCOS (NCT02502266)					Cediranib + olaparib vs cediranib vs SOC CT (physician’s choice)	Recurrent, platinum-resistant/refractory OvCA (high-grade for BRCA1/2 non-mutation carriers)	Randomized, open-label, phase III	PFS, OS
OCTOVA (NCT03117933)					Olaparib + cediranib vs olaparib vs paclitaxel	Platinum-resistant OvCa	Randomized, open-label, phase II	PFS
PARPi + anti-PD-1/PD-L1 antibody combinations
TOPACIO/KEYNOTE-162 (NCT02657889)					Niraparib + pembrolizumab	Recurrent OvCa	Open-label, phase I–II	ORR
Javelin PARP Medley (NCT03330405)					Talazoparib + avelumab	Recurrent, platinum-sensitive including BRCA-mutated OvCa	Open-label, phase Ib-II	ORR
NCT02660034					BGB-290 (pamiparib) + BGB-A317 (tislelizumab)	Recurrent, platinum-sensitive (TFIp >6) mos), high-grade OvCa	Open-label, phase I	ORR
ARIES (NCT03824704)					Rucaparib + nivolumab	Relapsed, platinum-sensitive OvCa	Open-label, phase II	ORR
NCT02484404					Olaparib + durvalumab	Recurrent, platinum-resistant OvCa	Open-label, phase II	ORR
PARPi + anti-PD-1/PD-L1 antibody + VEGFRi combinations
NCT02484404					Durvalumab + olaparib + cediranib, durvalumab + olaparib, and durvalumab + cediranib	Recurrent, platinum-sensitive or resistant OvCa	Non-randomized, open-label, phase II	ORR
MEDIOLA (NCT02734004)					Durvalumab + olaparib + bevacizumab and durvalumab + olaparib	Relapsed, platinum-sensitive OvCa	Non-randomized, open-label, phase II	ORR
NCT02873962					Nivolumab + rucaparib + bevacizumab, nivolumab + bevacizumab	Relapsed, platinum-sensitive or resistant OvCa	Non-randomized, open-label, phase II	ORR
NSGO/AVANOVA-Triplet (NCT03806049)					TSR-042 + niraparib + bevacizumab, niraparib + bevacizumab, and carboplatin + paclitaxel	Recurrent, platinum-sensitive OvCa	Randomized, open-label, phase III	PFS
OPAL (NCT03574779)					TSR-042 + niraparib + bevacizumab	Recurrent, platinum-resistant OvCa	Open-label, phase II	ORR
anti-PD-1/PD-L1 antibody + VEGFRi combination
NCT04068974					Camrelizumab + apatinib	Recurrent, platinum-resistant OvCa	Open-label, phase II	ORR

^aClinical trials may include patients with other tumor types in addition to patients with advanced ovarian cancer. A: angiogenesis inhibition, bev: bevacizumab, CT: chemotherapy, m: maintenance, EP: endpoint, I: PD-1/PD-L1 immune checkpoint inhibition, ORR: objective response rate, OS: overall survival, OvCa: ovarian cancer, P: PARP inhibition, PARPi: PARP inhibitor, PD-1: programmed death 1 receptor, PD-L1: PD-ligand 1, PFS: progression-free survival, SOC: standard of care, TFIp: platinum treatment-free interval, VEGFRi: vascular endothelial growth factor receptor inhibitor.

Table 5. Targeted agents in development for the treatment of patients with advanced ovarian cancer

Agent	Target/MOA	Structure	Company	Phase
Folate receptor α (FRα) targeting
Mirvetuximab soravtansine (IMGN853) (M9346A antibody + maytansinoid DM4)	FRα/microtubule inhibitor	ADC	ImmunoGen	I–III
MORAb-202 (farletuzumab + eribulin)	FRα/microtubule inhibitor	ADC	Eisai	I–II
Tissue factor targeting
Tisotumab vedotin (HuMax-TF-ADC) (antibody + MMAE)	Tissue factor targeting/microtubule inhibitor	ADC	Genmab/Seattle Genetics	II
PTK7 targeting
PF-06647020 (antibody + auristatin 0101)	PTK7 targeting/microtubule inhibitor	ADC	Pfizer/AbbVie	I
Protein kinase inhibition
Adavosertib (AZD1775)	WEE1 TK inhibitor	SMI	AstraZeneca	II
Alpelisib (BYL719)	PI3K-α inhibitor	SMI	Novartis	Ib
Ralimetinib (LY2228820 dimesylate)	p38 MAPK1 inhibitor	SMI	Lilly	Ib/II
Prexasertib (LY2606368)	CHK 1/2 inhibitor	SMI	Lilly	II
AZD6738	ATR PK inhibitor	SMI	AstraZeneca	II
Berzosertib (M6620, VX-970/VE-822)	ATR PK inhibitor	SMI	Merck Serono	II

ADC: antibody-drug conjugate, ATR: ataxia telangiectasia mutated and Rad3-related kinase, CHK: cell cycle checkpoint, FGF: fibroblast growth factor, HDAC: histone deacetylase, Hsp: heat shock protein, MAPK: mitogen-activated protein kinase, MMAE: monomethyl auristatin E, MOA: mechanism of action, PDGF: platelet-derived growth factor, PI3K: phosphatidylinositol 3-kinase, PK: protein kinase, SMI: small-molecule inhibitor, TK: tyrosine kinase, VEGF: vascular endothelial growth factor, VEGFR2: VEGF receptor 2.

Table 6. Clinical trials evaluating emerging agents for the treatment of patients with advanced ovarian cancer

Clinical Trial	Treatment	Patient Population^a	Phase	Primary EP
Targeting folate receptor α (FRα)
FORWARD I (NCT02631876)	Mirvetuximab soravtansine vs CT of choice (paclitaxel, pegylated liposomal doxorubicin or topotecan)	Platinum-resistant, FRα-positive OvCa	Randomized, open-label phase III	PFS
MIRASOL (NCT04209855)	Mirvetuximab soravtansine vs CT of choice (paclitaxel, pegylated liposomal doxorubicin, or topotecan)	Platinum-resistant OvCa with high FRα expression	Randomized, open-label phase III	PFS
SORAYA (NCT04296890)	Mirvetuximab soravtansine	Platinum-resistant OvCa with high FRα expression	Single-arm, open-label phase III	ORR
KEYNOTE PN409/FORWARD II (NCT02606305)	Mirvetuximab soravtansine + carboplatin or bev or pegylated liposomal doxorubicin or pembrolizumab or carboplatin/bev	FRα-positive OvCa	Phase Ib-II	ORR
NCT03552471	Mirvetuximab soravtansine + rucaparib	FRα-positive, recurrent BRCA-mutated or platinum-resistant OvCa	Phase I	RP2D
NCT04300556	Morab-202	FRα-positive, platinum-resistant OvCa and other solid tumors	Phase I–II	Safety, RP2D, ORR
Tissue factor (TF) targeting
NCT02552121	Tisotumab vedotin	Relapsed/metastatic tumors known to express TF	Phase I–II	Safety, RP2D
InnovaTV 208 (NCT03657043)	Tisotumab vedotin (standard or dose-dense regimen)	Platinum-resistant OvCa	Randomized, open-label phase II	ORR
Protein kinase inhibition
NCT03579316	Adavosertib single agent or + olaparib	Recurrent OvCa with progression after prior PARPi therapy	Randomized, open-label phase II	ORR
NCI MATCH screening trial/subprotocol Z1I BRCA-mutated tumors (NCT02465060)	Single-agent adavosertib	Advanced, BRCA-mutated, refractory OvCa	Phase II	ORR
NCT01623349	Alpelisib (BYL 719) or buparlisib (BKM120) + olaparib	Recurrent high-grade OvCa after prior platinum-based therapy	Phase Ib	MTD, RP2D
NCT01663857	Ralimetinib + CT (gemcitabine and carboplatin) vs CT	Recurrent OvCa, TFIp >6 months	Randomized, double-blind, phase Ib-II	PFS
NCT02203513	Prexasertib (LY2606368)	Recurrent BRCA-mutated and BRCA-non mutated OvCa	Phase II	ORR
NCT03414047	Prexasertib (LY2606368)	Recurrent, BRCA-mutated and BRCA-non mutated, platinum resistant/refractory OvCa	Phase II	ORR
CAPRI (NCT03462342)	AZD6738 + olaparib	Recurrent platinum-sensitive and platinum-resistant OvCa	Phase II	Safety
NCT02595892	Berzosertib (M6620) + gemcitabine vs gemcitabine	Recurrent, platinum-resistant OvCa	Randomized, open-label phase II	PFS
NCT02627443	Berzosertib (M6620) + carboplatin and gemcitabine	Recurrent, platinum-sensitive OvCa	Phase I	MTD, safety

^aClinical trials may include patients with other tumor types in addition to advanced ovarian cancer. AE: adverse event, Bev: bevacizumab, CT: chemotherapy, DLT: dose-limiting toxicity, EP: endpoint, MTD: maximum tolerated dose, ORR: objective response rate, OvCa: ovarian cancer, PARPi: PARP inhibitor, PFS: progression-free survival, q2 weeks: every 2 weeks, q3 weeks: every 3 weeks, RP2D: recommended phase II dose, SOC: standard of care, TFIp: platinum treatment-free interval.