Current status and future prospects of PARP inhibitor clinical trials in ovarian cancer

Figures & data

Table 1 Approval indications, dosing, dissociation constant (Ki), and relative trapping capacity of PARP inhibitors^17–25

Drug	Time of approval	Agency	Population	BRCA status	Clinical Setting	Dosing	Ki	Relative trapping capacity
Olaparib capsule	December 2014	EMA	Platinum-sensitive relapsed HGSOC, post CR/PR	g/sBRCAm	Maintenance	400mg BID	PARP1:5nM PARP2:1nM	+++
December 2014	FDA	Advanced OC	gBRCAm	Fourth line
Olaparib tablet	August 2017	FDA	Recurrent OC, post CR/PR	－	Maintenance	300mg BID
	Advanced OC	gBRCAm	Fourth line
February 2018	EMA	Platinum-sensitive relapsed HGOC, post CR/PR	－	Maintenance
Rucaparib	December 2016	FDA	Advanced OC	g/sBRCAm	Third line	600mg BID	PARP1:1.4nM	+++
	Recurrent OC, post CR/PR	－	Maintenance
May 2018	EMA	Platinum-sensitive relapsed/progressive HGOC	g/sBRCAm	Third line
Niraparib	March 2017	FDA	Recurrent OC, post CR/PR	－	Maintenance	300mg QD	PARP1:3.2nM PARP2:4.0nM	++++
November 2017	EMA	Platinum-sensitive relapsed HGSOC, post CR/PR	－	Maintenance
Veliparib	－	－	－	－	－	300mg BID	PARP1:5.2nM PARP2:2.9nM	+
Talazoparib	－	－	－	－	－	1.0mg QD	PARP1:1.2nM PARP2:0.9nM	+++++

Note: The relative trapping capacity of the PARP inhibitors is talazoparib (+++++) ＞niraparib (++++)＞olaparib (+++) and rucaparib (+++)＞veliparib (+).

Abbreviations: FDA, Food and Drug Administration; EMA, European Medicine Agency; BRCA, breast cancer susceptibility gene; PARP, poly (ADP-ribose) polymerase; CR/PR, complete response or partial response; g/sBRCAm, germline and/or somatic BRCA1/2 mutation; OC, epithelial ovarian, fallopian tube or primary peritoneal cancer; HGOC, High-grade epithelial ovarian, fallopian tube or primary peritoneal cancer; HGSOC, High-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer; QD, once daily; BID, twice daily.

Table 2 Clinical trials with PARP inhibitors (olaparib, rucaparib, niraparib) therapy in ovarian cancer

Drug	Clinical Trial Phase	Clinical setting	Population	Design	Results/Status
Olaparib	II Study 42 (NCT 01078662)	Platinum-resistant relapse	gBRCAm advanced OC or unsuitable for further platinum therapy	Non Randomized, Non Comparative Olaparib capsules 400mg po bid	ORR 31% Median PFS 7.0 ms Median OS 16.6 ms
	II Study19 (NCT00753545)	Platinum-sensitive relapse maintenance	HGSOC following ≥2 platinum-based chemo with CR/PR to last platinum	Randomized Olaparib capsules 400mg po bid vs placebo	Median PFS -Overall 8.4 vs 4.8 ms (p<0.001) -BRCAm 11.2vs 4.3 ms (p<0.0001) -BRCAwt 7.4vs 5.5 ms (p=0.0075) Median OS -Overall 29.8 vs 27.8 ms (N.S.) -BRCAm 34.9 vs 30.2 ms (N.S.) -BRCAwt 24.5 vs 26.6 ms (N.S.)
	III SOLO1 (NCT01844986)	First-line maintenance	Stage III/IV BRCAm HGS/EOC with CR/PR to initial first-line platinum-based chemo	Randomized Olaparib tablets 300mg po bid vs placebo	Median PFS BRCAm NR vs 13.8 ms (p<0.0001)
	III SOLO2 (NCT01874353)	Platinum-sensitive relapse maintenance	BRCAm HGS/EOC following ≥2 platinum-based chemo with CR/PR to last platinum	Randomized Olaparib tablets 300mg po bid vs placebo	Median PFS BRCAm 19.1vs 5.5 ms (p<0.0001)
	II (NCT01081951)	Platinum-sensitive relapse	HGSOC following≤3 platinum-based chemo with progression free for ≥6 months	Randomized [Paclitaxel (175mg/m^2) + carboplatin(AUC=4) iv + olaparib capsules 200mg bid po, 1–10 days/21 days, 4–6 cycles] + olaparib capsules 400 mg bid po vs Paclitaxel (175mg/m^2)+ carboplatin(AUC =6) iv/21 days, 4–6 cycles	Median PFS -Overall 12.2 vs 9.6 ms (p=0.0012) -BRCAm NR vs 9.7 ms (p=0.0015) Median OS -Overall 33.8 vs 37.6 ms (N.S.) -BRCAm NR vs 39.2 ms (N.S.)
II (NCT00628251)	Platinum-sensitive and resistant relapse	gBRCAm OC Relapsed within 12 months of prior platinum	Randomized Olaparib capsules 200 mg/400 mg po bid vs PLD 50 mg/m^2 iv/4 weeks	Median PFS 6.5/8.8 vs 7.1 ms(N.S.) ORR 25%/31% vs18%(N.S.)
	II (NCT01116648)	Platinum-sensitive relapse	HGS/EOC or gBRCAm HGOC with any number of platinum-based chemo and ≤1 non-platinum therapy with response to last platinum	Randomized Olaparib capsules 200mg po bid + cediranib 30 mg po qd vs olaparib capsules 400 mg po bid	ORR -Overall 79.6% vs 47.8%(p=0.002) Median PFS -Overall 17.7 vs 9.0 ms(p=0.005) -gBRCAm 19.4 vs 16.5 ms (N.S.) -BRCAwt 16.5 vs 5.7 ms (p=0.008)
Rucaparib	I/II Study 10 (NCT01482715)	-Part 2A Platinum-sensitive relapse -Part 2B Platinum-sensitive /resistant/refractory relapse	-Part 2A gBRCAm HGOC with 2–4 prior regimens, PFS ≥6 ms after last platinum -Part 2B g/sBRCAm HGOC with 3–4 prior regimens	Non Randomized, Non Comparative Rucaparib 600mg po bid	-Part 2A ORR 59.5% -Part 2B ongoing
	II ARIEL 2 (NCT 01891344)	-Part 1 Platinum-sensitive relapse -Part 2 Platinum-sensitive /resistant/refractory relapse	-Part 1 HGOC≥1 prior platinum-based chemo -Part 2 HGOC with 3–4 prior chemo, treatment-free>6 ms after first-line chemo	Non Randomized Rucaparib 600mg po bid	Part 1 Median PFS -BRCAm 12.8 ms (p<0.0001) -LOH high 5.7 ms (p=0.011) -LOH low 5.2 ms (reference) Part 2 Ongoing
	Study 10(Part 2A)+ARIEL 2(Parts 1 and 2)	Platinum-sensitive /resistant/refractory relapse	HGOC gBRCAm(Study 10) or g/sBRCAm(ARIEL2) with ≥2 prior platinum-based chemo	Non Randomized, Non Comparative Rucaparib 600mg po bid	ORR 53.8% Median DOR 9.2 ms
III ARIEL 3 (NCT01968213)	Platinum-sensitive relapse maintenance	HGS/EOC ≥2 prior platinum-based chemo with CR/PR to last platinum, CA125<upper limit of normal, with ≥4 cycles last platinum-based doublet chemo	Randomized Rucaparib 600mg po bid vs placebo	Median PFS -BRCAm 16.6 vs 5.4 ms (p<0.0001) -HRD 13.6 vs 5.4 ms (p<0.0001) -Intention-to-treat population 10.8 vs 5.4 ms (p<0.0001)
Niraparib	III NOVA (NCT01847274)	Platinum-sensitive relapse maintenance	HGSOC following ≥2 platinum-based regimens with ≥4 cycles last platinum-based chemo and CR/PR to last platinum with residual disease<2cm	Randomized Niraparib 300mg po qd vs placebo	Median PFS -gBRCAm 21.0 vs 5.5 ms (p<0.001) -HRD 12.9 vs 3.8 ms (p<0.001) -BRCAwt 9.3 vs 3.9 ms (p<0.001)

Abbreviations: BRCAwt, BRCA wild-type; N.S., no significance; ms, months; OC, epithelial ovarian, fallopian tube or primary peritoneal cancer; EOC, epithelial ovarian cancer; HGOC, High-grade epithelial ovarian, fallopian tube or primary peritoneal cancer; HGSOC, High-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer; HGS/EOC, High-grade serous or endometrioid epithelial ovarian, fallopian tube or primary peritoneal cancer; CR/PR, complete response or partial response; g/sBRCAm, germline or somatic BRCA1/2 mutation; PLD, Pegylated liposomal doxorubicin. PFS, Progression-free survival; OS, overall survival; HRD, homologous recombination deficiency; ORR, objective response rate; NR, not reached; AUC, area under curve; LOH, loss of heterozygosity; DOR, duration of response; po, orally; iv, intravenous; vs, versus; qd, once daily; bid, twice daily.

Table 3 The safety profiles of PARP inhibitors (olaparib, rucaparib and niraparib) in clinical trials^{27,31,36,39–43,45}

Drugs	Study	Grade 3/4 AEs	Dose interruption	Dose reduction	Dose discontinuation	MDS/AML	Treatment related deaths
Olaparib	Study2/24/9/ 12/20/42(n=223)	54%	40%	4%	7%	2%	3.6%
	Study19(n=136)	35.3%	27.9%	22.8%	2.2%	2%	0%
	SOLO2(n=195)	36%	45%	25%	11%	2%	1%
	SOLO1(n=260)	39%	52%	28%	12%	1%	0%
Rucaparib	ARIEL2 + Study10(n=377)	60.7%	58.6%	45.9%	10%	0.5%	0%
	ARIEL3(n=372)	56%	64%	55%	13%	1%	1%
Niraparib	NOVA(n=367)	64.6%	68.9%	66.5%	14.7%	1.4%	0.3%

Abbreviations: AEs, Adverse Events; MDS/AML, myelodysplastic syndrome/acute myeloid leukemia; PARP, poly (ADP-ribose) polymerase.

Table 4 The adverse events rates of PARP inhibitors (olaparib, rucaparib and niraparib) in clinical trials^{27,31,36,39–43,45}

Grade 3/4 AEs	Olaparib				Rucaparib		Nirparib
Study2/24/9/12/20/42 (n=223)	Study 19 (n=136)	SOLO2 (n=195)	SOLO1 (n=260)	ARIEL2 + Study10 (n=377)	ARIEL3 (n=372)	NOVA (n=367)
Anemia	15%	5.1%	19%	22%	24.9%	19%	25.3%
Neutropenia	-	-	5%	9%	9.8%	7%	19.6%
Thrombocytopenia	-	-	1%	1%	4.5%	5%	33.8%
Fatigue/asthenia	7%	7.3%	4%	4%	10.9%	7%	8.2%
Nausea	3%	2.2%	3%	1%	5.0%	4%	3.0%
Vomiting	4%	2.2%	3%	＜1%	4.0%	4%	1.9%

Abbreviations: AEs, Adverse Events; PARP, poly (ADP-ribose) polymerase.

Table 5 The critical ongoing trials on PARP inhibitors in ovarian cancer

Drug	Trial	Phase	Design
Olaparib	NCT02282020 SOLO3	III	Randomized Olaparib tablets 300mg po bid vs physician choice single agent non-platinum based chemo for gBRCAm Platinum-sensitive relapsed HGS/EOC following ≥2 platinum-based chemo with progression ≥6 months after last platinum
	NCT02446600	III	Randomized Platinum-base chemo(carboplatin + paclitaxel; carboplatin + gemcitabine; carboplatin + PLD) vs olaparib vs olaparib + cediranib for Platinum-sensitive relapsed HGS/EOC or gBRCAm HGOC with any number of platinum-based chemo and ≤1 non-platinum therapy with CR to last platinum
	NCT02502266	II/III	Randomized Physician choice chemo(paclitaxel; PLD; topotecan) vs olaparib + cediranib vs olaparib vs cediranib for Platinum-resistant or refractory relapsed, HGS/EOC non-gBRCAm or HGOC gBRCAm with ≤3 prior regimens and ≤1 non-platinum
	NCT02889900 CONCERTO	IIb	Non Randomized, Non Comparative Cediranib + Olaparib for recurrent platinum resistant ovarian cancer without gBRCAm
	NCT03106987 OReO	IIIb	Randomized olaparib vs placebo maintenance re-treatment for relapsed non-mucinous EOC, who have had disease progression following maintenance therapy with a PARPi and a CR/PR to subsequent platinum-based chemotherapy
	NCT02855697 MOLTO	I	Non Randomized, Non Comparative multi-maintenance olaparib for platinum sensitive relapsed gBRCAm HGS/EOC with 2 or more courses of maintenance olaparib
	NCT03402841 OPINION	IIIb	Non Randomized, Non Comparative olaparib maintenance for platinum sensitive relapsed non gBRCAm HGS/EOC
	NCT02340611	II	Non Randomized, Non Comparative Cediranib+Olaparib after disease progression on olaparib alone in OC
	NCT03278717ICON 9	III	Randomized maintenance olaparib + cediranib vs olaparib alone for relapsed OC with disease progressed more than 6 months after first line chemotherapy or CR/PR to ≥4 cycles of platinum based chemotherapy.
	NCT03470805	II	Non Randomized, Non Comparative Olaparib maintenance after response to Trabectedin-PLD in recurrent gBRCAm or sBRCAm HGS/EOC
	NCT03117933 OCTOVA	II	Randomized Olaparib vs Olaparib + Cediranib vs weekly paclitaxel for BRCAm platinum-resistant OC
	NCT03161132 ROLANDO	II	Non Randomized, Non Comparative Olaparib + PLD for platinum resistant advanced OC
	NCT01623349	I	To determine the safety of Oral PI3kinase Inhibitor BKM120 or BYL719 + Olaparib for recurrent HGSOC
	NCT01650376	Ib	To determine the MTD of olaparib + weekly carboplatin and paclitaxel in relapsed OC
	NCT03314740 BAROCCO	II	Randomized weekly paclitaxel vs cediranib-olaparib with continuous schedule vs cediranib-olaparib with intermittent schedule for platinum refractory or resistant recurrent HGSOC
	NCT02983799	II	Non Randomized, Non Comparative Olaparib for platinum-sensitive or partially platinum-sensitive, relapsed, HGS/EOC with at least 1 prior line of platinum-based chemotherapy, in gBRCAm, sBRCAm, or HRD subgroups
	NCT02571725	I-II	Non Randomized, Non Comparative Olaparib and CTLA-4 Blockade Tremelimumab for BRCAm recurrent OC
	NCT02477644 PAOLA-1	III	Randomized olaparib vs placebo for advanced FIGO stage IIIB - IV HGS/EOC with standard first-line platinum-taxane chemotherapy and bevacizumab concurrent and in maintenance, ≥3 cycles of bevacizumab in combination with the 3 last cycles of platinum-based chemotherapy
	NCT01445418	I	Non Randomized, Non Comparative olaparib + carboplatin for gBRCAm and sporadic OC
	NCT03462342 CAPRI	II	Non Randomized, Non Comparative ATR inhibitor AZD6738 + olaparib for recurrent HGSOC (platinum-sensitive or -resistant)
	NCT03579316	II	Randomized Non-Comparative adavosertib AZD1775 alone or with olaparib for recurrent OC during olaparib progression
	NCT03699449 AMBITION	II	Randomized olaparib+cediranib, durvalumab + olaparib, durvalumab + chemotherapy, durvalumab + tremelimumab + chemotherapy; a biomarker-driven targeted therapy for HRD platinum-resistant recurrent OC
	NCT02345265	II	Non Randomized, Non Comparative olaparib + cediranib for recurrent OC
	NCT02121990	I	Dose-escalation study of IP cisplatin, IV/IP paclitaxel, IV bevacizumab, and oral olaparib for newly diagnosed OC
	NCT02489006 NEO	II	Randomized, neoadjuvant olaparib for platinum sensitive recurrent HGSOC prior to surgery and chemotherapy
	NCT02953457	I/II	Non Randomized, Non Comparative olaparib together with durvalumab and tremelimumab for gBRCAm recurrent or refractory OC
	NCT02898207	I	To determine the safety and best dose of olaparib + HSP90 inhibitor onalespib for recurrent OC
	NCT01116648	I/II	To determine the safety and best dose of cediranib + olaparib for recurrent OC
	NCT02208375	Ib	To determine the MTD of olaparib + oral mTORC1/2 inhibitor AZD2014 or AKT inhibitor AZD5363 for recurrent OC
Rucaparib	NCT02855944 ARIEL 4	III	Randomized rucaparib 600mg po bid vs chemotherapy (carboplatin/paclitaxel, carboplatin/gemcitabine, cisplatin/gemcitabine, paclitaxel, carboplatin, cisplatin) for relapsed or progressing BRCAm HGOC ≥2 prior regimens
	NCT03522246 ATHENA	III	Randomized rucaparib and nivolumab as maintenance treatment following Response to front-line platinum-based chemotherapy in newly-diagnosed ovarian cancer
	NCT03462212 MITO25	II	Randomized first line therapy of carboplatin-paclitaxel-bevacizumab (in combination and maintenance) vs carboplatin-paclitaxel-bevacizumab-rucaparib (rucaparib only in maintenance) vs carboplatin-paclitaxel-rucaparib (rucaparib only in maintenance) on PFS in patients with advanced HGOC.
NCT03552471	I	To determine the safety and best dose of mirvetuximab soravtansine and rucaparib camsylate for recurrent OC
Niraparib	NCT02354586 QUADRA	II	Non Randomized, Non Comparative niraparib 300mg po qd for platinum-resistant or heavily pretreated HGSOC following 3 or 4 prior regimens, a response ≥6ms to first-line platinum based chemo
	NCT02655016 PRIMA	III	Randomized niraparib 300mg po qd vs placebo for first-line maintenance HGS/EOC stage III-IV with CR/PR to front-line platinum-based chemo
	NCT02354131 AVANOVA	I/II	Randomized niraparib vs bevacizumab-niraparib for platinum-sensitive relapsed HGS/EOC
	NCT03326193	II	Non Randomized, Non Comparative bevacizumab-niraparib for first-line maintenance HGS/EOC with CR/PR to front-line platinum-based chemo + bevacizumab≥1 debulking surgery
	NCT03602859 FIRST	III	Standard platinum-based chemo + Randomized [TSR-042 (anti-PD-1 antibody) + (niraparib + TSR-042) maintenance vs placebo + (niraparib + placebo) maintenance vs placebo + (placebo + placebo) maintenance for first line treatment of newly diagnosed stage III or IV non mucinous ovarian cancer
	NCT03574779 OPAL	II	To determine the safety and efficacy of niraparib + TSR-042 + bevacizumab for recurrent OC
	NCT03695380	Ib	Randomized, Non Comparative cobimetinib + niraparib ± atezolizumab for advanced platinum-sensitive OC
	NCT03598270 ANITA	III	Randomized platinum-based chemotherapy ± atezolizumab + niraparib maintenance ± atezolizumab maintenance for recurrent OC and platinum treatment-free interval >6 months
	NCT02657889 TOPACIO	I/II	Non Randomized, Non Comparative niraparib + pembrolizumab for recurrent OC
	NCT03586661	Ib	To determine the best dose and safety of niraparib and copanlisib for recurrent OC
	NCT03651206	II/III	Randomized (TSR-042 + niraparib vs niraparib) vs chemotherapy for metastatic or recurrent ovarian carcinosarcoma after first line chemotherapy
	NCT03154281	I	To determine the safety of niraparib + everolimus for advanced OC
Veliparib	NCT01113957	II	Randomized veliparib + temozolomide vs PLD for recurrent HGSOC
	NCT02470585	III	Randomized carboplatin/paclitaxel + veliparib or placebo + veliparib or placebo maintenance for newly diagnosed HGSOC (stage III or IV)
	NCT01012817	I/II	To determine the safety and best dose of veliparib + topotecan for relapsed or refractory OC after prior platinum containing first-line chemotherapy
	NCT01459380	I	To determine the safety and best dose of veliparib + PLD + carboplatin + bevacizumab for recurrent OC
	NCT01145430	I	To determine the safety and best dose of veliparib + PLD for recurrent OC
	NCT01749397	I	To determine the safety and best dose of veliparib + floxuridine for metastatic OC
	NCT00892736	I	To determine the safety and best dose of veliparib for BRCAm cancer or platinum-refractory OC
	NCT00989651	I	To determine the safety and best dose of intravenous carboplatin/paclitaxel or intravenous and intraperitoneal paclitaxel/cisplatin in combination with continuous or intermittent veliparib and bevacizumab for newly diagnosed stage II-IV OC
Talazoparib	NCT03642132	III	Randomized avelumab + chemotherapy + maintenance of avelumab + talazoparib for untreated advanced OC
	NCT02326844	II	Non Randomized, Non Comparative talazoparib for BRCAm OC with prior PARP inhibitor treatment
	NCT03330405	Ib/II	To evaluate safety and anti-tumor activity of avelumab + talazoparib for recurrent platinum sensitive OC

Abbreviations: OC, epithelial ovarian, fallopian tube or primary peritoneal cancer; EOC, epithelial ovarian cancer; HGOC, High-grade epithelial ovarian, fallopian tube or primary peritoneal cancer; HGSOC, High-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer; HGS/EOC, High-grade serous or endometrioid epithelial ovarian, fallopian tube or primary peritoneal cancer; CR/PR, complete response or partial response; MTD, maximum-tolerated dose; g/sBRCAm, germline or somatic BRCA1/2 mutation; PLD, Pegylated liposomal doxorubicin. PFS, Progression-free survival; HRD, homologous recombination deficiency.

AstraZeneca AB. Lynparza 50 mg hard capsules: EU summary of product characteristics; 2014 Available from: https://www.ema.europa.eu/documents/product-information/lynparza-epar-product-information_en.pdf. Accessed 19, 2015.

 Google Scholar

Tesaro. Zejula 100 mg hard capsules: EU summary of product characteristics. 2017 Available from: https://www.ema.europa.eu/documents/product-information/zejula-epar-product-information_en.pdf. Accessed 11, 27 2017.

 Google Scholar

Matulonis UA, Penson RT, Domchek SM, et al. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Ann Oncol. 2016;27:1013–1019. doi:10.1093/annonc/mdw13326961146

 PubMed Web of Science ®Google Scholar

Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382–1392. doi:10.1056/NEJMoa110553522452356

 PubMed Web of Science ®Google Scholar

Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274–1284. doi:10.1016/S1470-2045(17)30469-228754483

 PubMed Web of Science ®Google Scholar

Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018. doi:10.1056/NEJMoa1810858

 Web of Science ®Google Scholar

Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:1949–1961. doi:10.1016/S0140-6736(17)32440-628916367

 PubMed Web of Science ®Google Scholar

Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154–2164. doi:10.1056/NEJMoa161131027717299

 PubMed Web of Science ®Google Scholar