Current status of poly(ADP-ribose) polymerase inhibitors and future directions

Figures & data

Table 1 Summary of Phase II/III trials of PARP inhibitors

Agent	Phase	Number of patients	Tumor type	ORR	Median PFS	Median OS
Olaparib^Citation31	2	50	Metastatic castration-resistant prostate cancer	33% (entire cohort), 88% (genomic defects positive cases in DNA-repair genes), 6% (genomic defects negative cases in DNA-repair genes)	9.8 months (genomic defects positive cases in DNA-repair genes), 2.7 months (genomic defects negative cases in DNA-repair genes)	13.8 months (genomic defects positive cases in DNA-repair genes), 7.5 months (genomic defects negative cases in DNA-repair genes)
Olaparib^Citation41	2	57	Recurrent BRCA-mutant ovarian cancer	33% (400 mg twice daily), 13% (100 mg twice daily)	5.8 months (400 mg twice daily), 1.9 months (100 mg twice daily)	Not reported
Olaparib^Citation42	2	298	Recurrent BRCA-mutant cancer	26% (entire cohort), 31% (ovarian), 13% (breast), 22% (pancreatic), 50% (prostate)	7.0 months (ovarian), 3.7 months (breast), 4.6 months (pancreatic), 7.2 months (prostate)	16.6 months (ovarian), 11 months (breast), 9.8 months (pancreatic), 18.4 months (prostate)
Olaparib^Citation43	2	64	Advanced HGSOC or TNBC	41% (BRCA mutant), 24% (BRCA wild)	7.2 months (ovarian), 1.8 months (breast)	Not reported
Olaparib^Citation44	2	265	Recurrent platinum-sensitive HGSOC	12% (olaparib), 4% (placebo)	8.4 months (olaparib), 4.8 months (placebo)	29.7 months (olaparib), 29.9 months (placebo)
Olaparib^Citation46	2	54	Recurrent BRCA-mutant breast cancer	41% (400 mg twice daily), 22% (100 mg twice daily)	5.7 months (400 mg twice daily), 3.8 months (100 mg twice daily)	Not reported
Rucaparib^Citation49	2	35	Recurrent BRCA-mutant ovarian cancer	65%	Not reached	Not reported
Rucaparib^Citation50	2	206	Recurrent platinum-sensitive high-grade ovarian cancer	80% (BRCA mutant), 29% (BRCA wild/LOH high), 10% (BRCA wild/LOH low)	12.8 months (BRCA mutant), 5.7 months (BRCA wild/LOH high), 5.2 months (BRCA wild/LOH low)	Not reported
Veliparib^Citation52	2	50	Persistent or recurrent BRCA-mutant epithelial ovarian, fallopian tube or primary peritoneal cancer	26%	8.2 months	Not reached
Niraparib^Citation54	3	553	Recurrent platinum-sensitive ovarian cancer	Not reported	21.0 months vs 5.5 months (germline BRCA mutant vs placebo), 12.9 months vs 3.8 months (BRCA wild/HRD positive vs placebo), 9.3 months vs 3.9 months (overall BRCA wild vs placebo)	Not reported

Abbreviations: PARP, poly(ADP-ribose) polymerase; ORR, overall response rate; PFS, progression-free survival; OS, overall survival; HGSOC, high-grade serous ovarian cancer; TNBC, triple-negative breast cancer; LOH, loss of heterozygosity; HRD, homologous recombination deficiency.

Table 2 Ongoing trials of PARP inhibitor combinations

PARP inhibitor	Combination agents	Phase	Types of malignancies	NCT identifier
Olaparib	AZD2014 (mTORC 1/2 inhibitor) or AZD5363 (AKT inhibitor)	I	Breast cancer, malignant female reproductive system tumors	NCT02208375
Olaparib	Prexasertib	I	Solid tumors	NCT03057145
Olaparib	AZD2281, AZD5363, AZD1775 or AZD2014	II	Tumors	NCT02576444
Olaparib	AT13387 (heat shock protein 90 inhibitor)	I	Ovarian cancer, fallopian tube cancer, peritoneal cancer and TNBC	NCT02898207
Olaparib	Cediranib, MEDI4736 (anti-PD-L1 antibody)	I/II	Lung cancer, breast cancer, ovarian cancer, colorectal cancer, prostate cancer and TNBC	NCT02484404
Olaparib	Temozolomide	I	Ewing sarcoma	NCT01858168
Olaparib	AZD1775 (tyrosine kinase WEE1 inhibitor)	I	Ovarian cancer, breast cancer and SCLC	NCT02511795
Olaparib	Temozolomide	I	Brain and central nervous system tumors	NCT01390571
Olaparib	CRLX101 (nanoparticle camptothecin)	I/II	SCLC	NCT02769962
Olaparib	Neoadjuvant carboplatin and paclitaxel	II/III	TNBC and germline BRCA-positive breast cancer	NCT03150576
Talazoparib	Decitabine	I/II	Acute myeloid leukemia	NCT02878785
Talazoparib	Temozolomide	I/II	Solid tumors	NCT02116777
Veliparib	VX-970 (ATR) and cisplatin	I	Tumors	NCT02723864
Veliparib	Intraperitoneal floxuridine	I	Fallopian tube cancer, ovarian cancer and primary peritoneal cancer	NCT01749397
Veliparib	Carboplatin and paclitaxel	III	BRCA-mutant breast cancer	NCT02163694
Veliparib	FOLFIRI or modified FOLFIRI	II	Pancreatic cancer	NCT02890355
Veliparib	Carboplatin and paclitaxel	III	Ovarian cancer, fallopian tube cancer and peritoneal cancer	NCT02470585
Veliparib	Topotecan hydrochloride	I/II	Solid tumors	NCT01012817
Niraparib	Temozolomide or irinotecan	I	Ewing sarcoma	NCT02044120
Niraparib	Pembrolizumab	I/II	Ovarian cancer, fallopian tube cancer, peritoneal cancer and TNBC	NCT02657889
Fluzoparib	Apatinib and paclitaxel	I	Gastric cancer	NCT03026881
Fluzoparib	Apatinib	I	Ovarian cancer and TNBC	NCT03075462
BGB-290	BGB-A317 (anti-PD-1 monoclonal antibody)	I	Solid tumors	NCT02660034

Abbreviations: FOLFIRI, folinic acid/fluorouracil/irinotecan; NCT, National Clinical Trial; PD-1, programmed death-1; PD-L1, programmed death-ligand1; TNBC, triple-negative breast cancer; SCLC, small cell lung cancer.

Table 3 Grade 3–4 toxicity profiles of PARP inhibitors

Grade 3–4 adverse events	Olaparib (n=298)^Citation42	Talazoparib (n=71)^Citation47	Rucaparib (n=204)^Citation50	Veliparib (n=50)^Citation52	Niraparib (n=367)^Citation54
Nausea	0%	0%	4%	4%	3%
Vomiting	2%	Not reported	2%	0%	2%
Fatigue	6%	Not reported	9%	Not reported	8%
Abdominal pain	6%	Not reported	2%	Not reported	1%
Thrombocytopenia	Not reported	18%	2%	2%	34%
Anemia	17%	23%	22%	0%	25%
Neutropenia	Not reported	10%	7%	2%	20%
Hypertension	Not reported	Not reported	Not reported	Not reported	8%
Increased AST/ALT	Not reported	Not reported	12%	Not reported	Not reported

Abbreviations: AST, aspartate transaminase; ALT, alanine aminotransferase; PARP, poly(ADP-ribose) polymerase.

Figure 1 Conceptual diagram of resistance mechanisms to PARP inhibitors.

Notes: These processes are categorized into three groups (recovery of HRR, decreased PARP-1 expression, and decreased intracellular PARP concentration due to activation of drug efflux). Secondary mutations in BRCA1/BRCA2, loss of 53BP1 and increased RAD51 finally result in recovery of HRR, where PTEN or Aurora A indirectly regulate RAD51 activity.
Abbreviations: PARP, poly(ADP-ribose) polymerase; HRR, homologous recombination repair.

Figure 2 Current indications for olaparib, rucaparib, and niraparib.

Notes: The differences among these agents, which are available under US health insurance, probably reflect the characteristics of patients who participated in the relevant clinical trials. Future investigations should be focused on HRR-proficient cases and malignancies other than ovarian, prostate and breast cancers.
Abbreviation: HRR, homologous recombination repair.

Figure 3 Current status of PARP inhibitors.

Notes: Recent advances in preclinical models have provided fundamental data on synthetic lethality and HRR pathways, and clinical trials have shown PFS prolongation with a focus on BRCA-mutant tumors. On the other hand, several issues remain, such as discovering new treatment targets for HRR-proficient cases or selecting the best agent in each clinical context. In the future, it will be important to demonstrate OS prolongation as a real clinical end point through development of PARP inhibitor combination regimens or neoadjuvant/adjuvant therapies.
Abbreviations: PARP, poly(ADP-ribose) polymerase; HRR, homologous recombination repair; PFS, progression-free survival; OS, overall survival.

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