Table 1.

Representative clinical trials of PARP inhibitors alone or in combination for the treatment of cancer.

TUMOR TYPE	PARP INHIBITOR	COMBINATION*	EXAMPLES OF BIOMARKERS ASSESSED	PERTINENT PRELIMINARY RESULTS
Ovarian	Olaparib	Nonea,b,c		Greater PFS benefit in BRCA1/2 mt vs. BRCA1/2 wt78
		Cediranib maleateb,c	BRCA1/2 mutation status (germline or somatic); BRCA1/2-HR assay
	Veliparib	Nonea,b,c		26% response rate. Median PFS: 8.18 months79
		Carboplatin, paclitaxel and bevacizumabf	BRCA1/2 mutation status (germline or somatic); changes in PARP inhibition in PBMCs
		Pegylated liposomal doxorubicin hydrochloride, carboplatin, and bevacizumabc	Germline mutations, alterations and/or rearrangements in BRCA1 or BRCA2
	Niraparib	Nonec	BRCA1/2 mutation status (germline); HRD status
		Bevacizumabc	BRCA1/2 mutation status
	Rucaparib	Nonec	HRD status (based on amount of genomic ‘scarring’ measured by extent of tumor genomic LOH)	ORR: 69% BRCA1/2 mt, 39% BRCA1/2 wt/LOH high, and 11% BRCA1/2 wt/LOH low patients34
Breast	Olaparib	None	BRCA1/2 mutation status
	Veliparib	Carboplatina,g	PARP1 activity
		Cyclophosphamide	PARP1 expression
	Talazoparib	Nonea,b	BRCA1/2 mutation status
Breast/Ovarian	Olaparib	Carboplatin		RR and median PFS of 36% and 3.5 months in platinum-sensitive, 6% and 4 months in platinum-resistant disease80
		PI3K inhibitor		Evidence of clinical benefit at all dose levels81
Prostate	Olaparib	Noned	BRCA1/2 mutation status (germline or somatic), ATM, FANCA, CHEK2, PALB2, HDAC2, RAD51, MLH3, ERCC3, MRE11, NBN mutation status; IHC levels of PAR, γ-H2AX, pH2A(s129), Rad51 foci, FancD2 foci and ATM/ATR/CHK1/CHK2	Antitumor activity of olaparib is significantly associated with DNA repair defects in the tumor69
	Veliparib	Temozolomide		Well tolerated with some anti-tumor activity82
		Abiraterone acetate and prednisone	PAR expression	97% concordance of ETS status between primary and metastatic site;83 Molecular profiling results65
CNS	Olaparib	Temozolomide	HRD status (by Rad51 foci); MSI status; MGMT methylation status; MMR, PTEN, γ-H2AX expression; PARP inhibition	Intratumoral levels of olaparib in recurrent GBM are therapeutic84
	Veliparib	Temozolomidee,f	Genetic or epigenetic alterations in PARP1, MGMT, and DNA repair or replication genes; NHEJ activity; MGMT methylation status	Combination well tolerated85
		Radiation and temozolomidef	PARP or NHEJ activity in PBMCs; γ-H2AX levels in PBMCs
Hematologic	Veliparib	Temozolomide	RAD51, y-H2AX foci, PAR levels, DSB repair, NHEJ repair
		Topotecan +/− carboplatin	PAR levels; mutation and/or expression of genes in select DNA repair pathways (Fanconi complementation groups A–F, Blooms, and ataxia-telangiectasia)
Pancreatic	Veliparib	+/− Gemcitabine and cisplatin	BRCA1/BRCA2/PALB2 mutation, genetic reversions of BRCA1/2 mutations, PAR levels
Gastro-intestinal	Olaparib	None	MSI status
	Veliparib	Capecitabine and radiationf		Combination well tolerated, promising preliminary antitumor activity86
Mixed Tumors	Olaparib	Nonea,b,c		Antitumor activity in germline BRCA1/2 mutation carriers with advanced ovarian cancer, including heavily pretreated, platinum-resistant cancers.87 Resistance to platinum decreases sensitivity to olaparib28
		AKT inhibitor	pERK, RAD51, BRCA1/2 and PARP expression
		Cediranib maleatea		Combination extended PFS and ORR, 44% ORR in ovarian cancer patients88
		mTORC1/2 or AKT inhibitor	Presence or absence of aberrations in PI3K/AKT/mTOR and HR defect pathway
	Veliparib	Nonea,b	BRCA1/2 expression, γ-H2AX, PAR expression and levels	Antitumor activity with veliparib in BRCA1/2-expressing tumors compared to BRCA1/2 wt TNBC89; Well-tolerated, antitumor activity in both BRCA1/2-expressing and BRCA1/2 wt tumors90
		Metronomic cyclophosphamide		Well tolerated combination; PAR significantly decreased in PBMCs and tumor; γ-H2AX levels increased91
		Topotecanb,c	ADP-ribose polymer formation, BRCA1/2 mutation status, levels of topoisomerase I, PARP, BRCA1, BRCA2, XRCC1, TDP1, P-glycoprotein and BCRP	Reduction in PAR levels in the tumor and PBMCs; increase in γ-H2AX levels in PBMCs92
		+/− Carboplatin and paclitaxela, or FOLFIRI	DNA repair defects; γ-H2AX and PAR levels; BRCA levels by IHC	Well tolerated combination, promising antitumor activity93
		+/− Mitomycin Ch	BRCA1/BRCA2 mutations, FancD2 foci formation, γ-H2AX foci
		Gemcitabinea	ATM levels in PBMCs
		Radiation	ERCC1, XRCC1, BRCA1, BRCA2, and PAR by IHC	Well tolerated combination, disease stability94
	Talazoparib	Nonea	BRCA1/2 mutation status (germline or somatic); BRCA1/2 somatic deletions; BRCA1/2 pathway gene alterations (ATM, PALB2, NBS1, Fanconi Anemia genes); PTEN deletion/mutation; HRD status (by LOH, TAI, and LST-Myriad test)	Antitumor activity in advanced previously treated SCLC and significant activity in patients with germline BRCA1/2 mutant ovarian and breast cancer95
	Rucaparib	Nonea		Well tolerated with promising clinical benefit in ovarian, breast, and pancreatic cancer96
	CEP-9722	+/− Temozolomide		Well tolerated combination97
Ewing Sarcoma	Olaparib	None		Safe and well tolerated98
Endometrial	Talazoparib	None	MSI; PTEN and MRE11 mutation status

Notes:

^*Treatment for advanced, metastatic tumors unless otherwise noted. For at least one trial with this treatment regimen:

^aBRCA1/2 mutations are an eligibility requirement,

^bplatinum resistant,

^cplatinum sensitive,

^dneoadjuvant treatment,

^eadjuvant treatment,

^ftreatment naïve,

^gHER2 negative,

^hFanconi anemia pathway deficient.

Abbreviations: DSB, double-strand break; GBM, glioblastoma multiforme; HR, homologous recombination; HRD, homologous recombination deficiency; IHC, immunohistochemistry; LOH, loss of heterozygosity; LST, large-scale state transitions; MSI, microsatellite instability; MT, mutant; NHEJ, nonhomologous end joining; ORR, overall response rate; OS, overall survival; PBMC, peripheral blood mononuclear cell; PFS, progression-free survival; RR, response rate; SCLC, small cell lung cancer; TAI, telomeric allelic imbalance; TNBC, triple negative breast cancer; WT, wild type; +/−, with or without.