Table Info

Table 1.

Clinical trials results for PARP Inhibitors in ovarian cancer

Study	Phase	Patients (n)	Setting	Treatment arms	Results	P-value
Recurrent/relapsed setting
STUDY 42 [8]	II	193	Recurrent pre-treaed advanced OC, BRCAmut	Olaparib 400 mg BID (capsules)	ORR: 34% MDR: 7.9 months
STUDY 19 [11] [12]	II	265	Platinum-sensitive recurrent HGSOC	Olaparib 400 mg BID (capsules) Placebo	Overall population: 8.4 vs. 4.8 months	P < 0.0001
STUDY 19 [11] [12]	II	265	Platinum-sensitive recurrent HGSOC	Olaparib 400 mg BID (capsules) Placebo	BRCAmut: 11.2 vs. 4.3 months	P < 0.0001
SOLO 2 [14]	III	295	Platinum-sensitive recurrent HGSOC or HGEOC, BRCAmut	Olaparib 300 mg BID Placebo	Median PFS
SOLO 2 [14]	III	295	Platinum-sensitive recurrent HGSOC or HGEOC, BRCAmut	Olaparib 300 mg BID Placebo	19.1 vs. 5.5 months	P < 0.0001
SOLO 3 [10]	III	266	Platinum-sensitive recurrent HGSOC BRCAmut	Olaparib 300 mg BID Single-agent nonplatinum chemotherapy (weekly paclitaxel, weekly topotecan, gemcitabine or pegylated liposomal doxorubicin)	ORR: 72.2% vs. 51.4	P = 0.002
NOVA [15]	III	553	Platinum-sensitive recurrent HGSOC	Niraparib 300 mg Placebo	Median PFS
					gBRCAmut: 21 vs. 5.5 months	P < 0.001
					BRCAwt HRD⁺: 12.9 vs. 3.8 months	P < 0.001
					Overall non-gBRCA: 9.3 vs. 3.9 months	P < 0.001
QUADRA [19]	II	45	Platinum sensitive HRD positive HGSOC	Niraparib 300 mg	ORR: 27.5% DCR: 68.6% DoR: 9.2 months
STUDY 10 [21]	I/II	42	Platinum-sensitive recurrent HGSOC or HGEOC, gBRCAmut (phase II PART 2A)	Rucaparib 600 mg BID	ORR: 59.5% MDR: 7.8 months
ARIEL 2 PART 1 [22]	II	192	Platinum sensitive recurrent HGSOC or HGEOC	Rucaparib 600 mg BID	Median PFS
					BRCAmut: 12.8 months	P < 0.0001
					BRCAwt LOH High: 5.7 months	P = 0.011
					BRCAwt LOH low: 5.2 months	P = 0.011
ARIEL 3 [24]	III	564	Platinum-sensitive recurrent HGSOC or HGEOC	Rucaparib 600 MG BID Placebo	Median PFS
					BRCAmut: 16.6 vs. 5.4 months	P < 0.0001
					HRD⁺: 13.6 vs. 5.4 months	P < 0.0001
					ITTP: 10.8 vs. 5.4 months	P < 0.0001
Front-line
SOLO1 [30]	III	391	FIGO Stage III/IV HGSOC or HGEOC BRCAmut	Olaparib 300 mg BID Placebo	BRCAmut: > 36 (NR) vs. 13.8 months	P < 0.0001 HR: 0.30 (95% CI 0.23–0.41)
PAOLA-1 [31]	III	806	FIGO Stage III/IV HGSOC or HGEOC	Bevacizumab: 15 mg/kg, q21 × 15 months, including when administered with chemotherapy + olaparib (300 mg BID) × 24 months Bevacizumab: 15 mg/kg, q21 × 15 months, including when administered with chemotherapy + Placebo × 24 months	Overall population ITT: 22.1 vs. 16.6 months	P < 0.0001 HR: 0.59 (95% CI 0.49–0.72)
					BRCAmut: 37.2 vs. 21.7 months	HR: 0.31 (95% CI 0.20–0.47)
					HRD (including BRCA): 37.2 months vs. 17.7 months	HR: 0.33 (95% CI 0.25–0.45)
					HRD (BRCAwt): 28.1 months vs. 16.6 months	HR: 0.43 (95% CI 0.28–0.66)
					HRP (BRCAwt): 16.9 months vs. 16.0	HR: 0.92 (95% CI 0.72–1.17)
PRIMA [32]	III	733	FIGO Stage III with residual tumor IV HGSOC or HGEOC	Niraparib 300 mg once daily, 36 months Placebo once daily, 36 months	Overall population: 13.8 vs. 8.2 months	P < 0.001 HR: 0.62 (95% CI 0.50–0.76)
					BRCAmut: 22.1 vs. 10.9 months	HR: 0.40 (95% CI 0.27–.62)
					HRD (including BRCA): 21.9 vs. 10.4 months	HR: 0.43 (95% CI 0.31–0.59)
					HRD (BRCAwt): 19.6 vs. 8.2 months	HR: 0.50 (95% CI 0.31–0.83)
					HRP (BRCAwt): 8,1 vs. 5.4 months	HR: 0.68 (95% CI 0.49–0.94)
VELIA [33]	III	1140	FIGO Stage III/IV HGSOC	Veliparib 150 BID in combination, 400 mg BID in maintenance	Overall population: 23.5 vs. 17.3 months	P < 0.001 HR: 0.68 (95% CI 0.56–0.83)
					BRCAmut: 34.7 vs. 22.0 months	HR: 0.44 (95% CI 0.28–0.68)
					HRD (including BRCA): 31.9 vs. 20.5 months	HR: 0.57 (95% CI 0.43–0.76)
					HRD (BRCAwt): 22.9 vs. 19.8 months	HR: 0.74 (95% CI 0.52–1.06)
					HRP (BRCAwt): 15.0 vs. 11.5 months	HR: 0.81 (95% CI 0.6–1.09)

NR: not reached; wt: wild type

Declarations

Author contributions

AP wrote the majority of the first draft of the manuscript; FC, CN, GS, DL and GD wrote sections of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

AP declared personal fees from AstraZeneca; GD declared advisory board from BeiGene and travel from Roche.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br J Cancer. 2016;115:1157–73. [DOI] [PubMed] [PMC]

Odell ID, Wallace SS, Pederson DS. Rules of engagement for base excision repair in chromatin. J Cell Physiol. 2013;228:258–66. [DOI] [PubMed] [PMC]

Helleday T, Bryant HE, Schultz N. Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle. 2005;4:1176–8. [DOI] [PubMed]

Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21. [DOI] [PubMed]

Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913–7. [DOI] [PubMed]

Bajrami I, Frankum JR, Konde A, Miller RE, Rehman FL, Brough R, et al. Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity. Cancer Res. 2014;74:287–97. [DOI] [PubMed] [PMC]

Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–34. [DOI] [PubMed]

Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244–50. [DOI] [PubMed] [PMC]

Domchek SM, Aghajanian C, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140:199–203. [DOI] [PubMed] [PMC]

10.

Penson RT, Valencia RV, Cibula D, Colombo N, Leath CA, Bidziński M, et al. Olaparib monotherapy versus (vs.) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial. J Clin Oncol. 2019;37 suppl 15:5506. [DOI]

11.

Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382–92. [DOI] [PubMed]

12.

Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15:852–61. [DOI] [PubMed]

13.

Ledermann JA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol. 2016;17:1579–89. [DOI] [PubMed]

14.

Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, 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;18:1274–84. [DOI] [PubMed]

15.

Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154–64. [DOI] [PubMed]

16.

Oza A, Matulonis U, Malander S, Sehouli J, Del Campo D, Berthon-Rigaud D, et al. Quality of life in patients with recurrent ovarian cancer (OC) treated with niraparib: results from the ENGOT-OV16/NOVA Trial. Annals of Oncology. 2017;28 suppl 5:v330–54.

17.

Matulonis UA, Herrstedt J, Tinker A, Marme F, Redondo A, Kalbacher E, et al. Long-term benefit of niraparib treatment of recurrent ovarian cancer (OC). J Clin Oncol. 2017;35 suppl 15:5534. [DOI]

18.

Berek JS, Matulonis UA, Peen U, Ghatage P, Mahner S, Redondo A, et al. Safety and dose modification for patients receiving niraparib. Ann Oncol. 2018;29:1784–92. [DOI] [PubMed]

19.

Moore KN, Secord AA, Geller MA, Miller DS, Cloven N, Fleming GF, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20:636–48. [DOI] [PubMed]

20.

Robillard L, Nguyen M, Harding TC, Simmons AD. In vitro and in vivo assessment of the mechanism of action of the PARP inhibitor rucaparib. Cancer Res. 2017;77 suppl 13:2475. [DOI]

21.

Kristeleit R, Shapiro GI, Burris HA, Oza AM, LoRusso P, Patel MR, et al. A phase I-II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors. Clin Cancer Res. 2017;23:4095–106. [DOI] [PubMed]

22.

Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18:75–87. [DOI] [PubMed]

23.

Oza AM, Tinker AV, Oaknin A, Shapira-Frommer R, McNeish IA, Swisher EM, et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol. 2017;147:267–75. [DOI] [PubMed]

24.

Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, 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;390:1949–61. [DOI] [PubMed] [PMC]

25.

Dockery LE, Gunderson CC, Moore KN. Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer. Onco Targets Ther. 2017;10:3029–37. [DOI] [PubMed] [PMC]

26.

Coleman RL, Sill MW, Bell-McGuinn K, Aghajanian C, Gray HJ, Tewari KS, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation – an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2015;137:386–91. [DOI] [PubMed] [PMC]

27.

de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov. 2017;7:620–9. [DOI] [PubMed] [PMC]

28.

Wainberg ZA, Hecht JR, Konecny GE, Goldman JW, Sadeghi S, Chmielowski B, et al. Safety and efficacy results from a phase I dose-escalation trial of the PARP inhibitor talazoparib in combination with either temozoomide or irinotecan in patients with advanced malignancies. Cancer Res. 2016;76 suppl 14:CT011. [DOI]

29.

Dhawan MS, Bartelink IH, Aggarwal RR, Leng J, Zhang JZ, Pawlowska N, et al. Differential toxicity in patients with and without DNA repair mutations: phase I study of carboplatin and talazoparib in advanced solid tumors. Clin Cancer Res. 2017;23:6400–10. [DOI] [PubMed]

30.

Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495–505. [DOI] [PubMed]

31.

Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381:2416–28. [DOI] [PubMed]

32.

González-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381:2391–402. [DOI] [PubMed]

33.

Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403–15. [DOI] [PubMed] [PMC]