Table 1.
Efficacy data for selected studies evaluating PARP inhibitor combinations in advanced solid tumours.
| Drug class | Reference (phase) | Treatment | Study population | Overall efficacy |
|---|---|---|---|---|
| Platinum chemotherapy | Ramalingam et al. (Phase 3) [141] | Carboplatin/paclitaxel +/− veliparib | Previously untreated advanced squamous cell lung cancer (n = 970) | Median PFS: 5.6 mo in both groups (carboplatin/paclitaxel with or without veliparib) |
| O’Reilly et al. (Phase 2) [142] | Gemcitabine/cisplatin +/− veliparib | Advanced pancreatic adenocarcinoma, germline BRCA1/2 or PALB2 mutation (n = 50) |
Median PFS: 10.1 mo (chemo + veliparib) vs 9.7 mo (chemo + placebo) ORR: 20/27 (74%) with veliparib vs 15/23 (65%) with placebo |
|
| Diéras et al. (Phase 3) [143] | Carboplatin/paclitaxel +/− veliparib | BRCA1/2-mutated advanced breast cancer (n = 513) | Median PFS: 14.5 mo (chemo + veliparib) and 12.6 mo (chemo) | |
| DNA alkylators | Pietanza et al. (Phase 2) [144] | Temozolomide +/− veliparib | Previously treated SCLC (n = 104) |
PFS at 4 months: 36% (TMZ/veliparib) and 27% (TMZ/placebo) ORR: 19/49 (39%) for TMZ/veliparib and 6/44 (14%) for TMZ/placebo |
| Plummer et al. (Phase 2) [136] | Temozolomide + rucaparib | Chemotherapy naive metastatic melanoma (n = 46) | ORR: 8/46 (17%) | |
| Pishvaian et al. (Phase 2) [131] | Temozolomide + velaparib | Treatment-refractory metastatic colorectal cancer (n = 50) | ORR: 2/50 (4%) | |
| Farago et al. (Phase 2) [132] | Temozolomide + olaparib | Previously treated small cell lung cancer (n = 48) | ORR: 20/48 (42%) | |
| Xu et al. (Phase 2) [133] | Temozolomide + olaparib | Metastatic breast cancer (n = 62) | ORR: 7/62 (12%) | |
| Topoisomerase Inhibitors | LoRusso et al. (Phase 1) [138] | Irinotecan + veliparib | Previously treated advanced solid tumours (n = 31) | ORR: 6/31 (19%) |
| Gorbunova et al. (Phase 2) [145] | 5-Fluorouracil/irinotecan +/− veliparib | Untreated metastatic colorectal cancer (n = 130) | Median PFS: 12 mo (FOLFIRI/veliparib) vs 11 mo (FOLFIRI) | |
| Yap et al. (Phase 1) [140] | Sacituzumab + rucaparib | Advanced solid tumours with or without mutations in HR genes (n = 6) | ORR: 3/6 (50%) | |
| Anti-VEGF | Liu et al. (Phase 3) [56] | Olaparib +/− cediranib versus platinum-based chemotherapy | Recurrent platinum-sensitive ovarian cancer (n = 565) | Median PFS: 10.3 mo (chemo), 8.2 mo (olaparib), and 10.4 mo (olaparib/cediranib) |
| Mirza et al. (Phase 2) [55] | Niraparib +/− bevacizumab | Recurrent platinum-sensitive ovarian cancer (n = 97) | Median PFS: 11.0 mo (niraparib/bevacizumab) and 5.5 mo (niraparib) | |
| Colombo et al. (Phase 2) [57] | Paclitaxel vs cediranib + olaparib (continuous or intermittent) | Recurrent platinum-resistant ovarian cancer (n = 123) | Median PFS: 3.1 mo (paclitaxel), 5.6 mo (continuous cediranib + olaparib), 3.8 mo (intermittent cediranib + olaparib) | |
| Lheureux et al. (Phase 2) [58] | Cediranib + olaparib | Treatment-refractory ovarian cancer with progression on PARPi (n = 34) | ORR: 3/34 (9%) | |
| Lee et al. (Phase 2) [59] | Cediranib + Olaparib | HRD-positive platinum-resistant ovarian cancer (n = 16) | ORR: 8/16 (50%) | |
| Ray-Coquard et al. (Phase 3) [54] | Bevacizumab +/− olaparib maintenance | Ovarian cancer responsive to first-line platinum chemotherapy (n = 806) | Median PFS: 22.1 mo (bevacizumab/olaparib) vs 16.6 mo (bevacizumab) | |
| Hardesty et al. (Phase 2) [146] | Bevacizumab + niraparib maintenance | Ovarian cancer responsive to first-line platinum chemotherapy (n = 105) | Median PFS: 19.6 months | |
| Cecchini et al. (Phase 1/2) [62] | Ramucirumab + olaparib | Refractory metastatic gastric or GEJ adenocarcinoma (n = 46) | ORR: 5/46 (11%) | |
| PI3K/AKT inhibitor | Batalini et al. (Phase 1) [46] | Alpelisib + olaparib | Advanced triple-negative breast cancer and recurrent breast cancer with gBRCA1/2 mutation (n = 17) | ORR: 3/17 (18%) |
| Konstantinopoulos et al. (Phase 1) [47] | Alpelisib + olaparib | Recurrent ovarian cancer with gBRCA1/2 mutation (n = 28) | ORR: 10/28 (36%) | |
| Yap et al. (Phase 1) [49] | Capivasertib + olaparib | Advanced solid tumours and gBRCA1/2 mutation or BRCA1/2 wild type with DDR or PI3K-AKT pathway alterations (n = 56) | ORR: 19/56 (34%) | |
| Westin et al. (Phase 1) [48] | Capivasertib + olaparib | Recurrent endometrial, ovarian, and triple-negative breast cancer (n = 32) | ORR: 6/32 (19%) | |
| EGFR inhibitor | Stringer-Reasor et al. (Phase 1) [74] | Veliparib + lapatanib | Metastatic triple-negative breast cancer without gBRCA1/2 mutation (n = 17) | ORR: 4/17 (24%) |
| MEK inhibitor | Kurnit et al. (Phase 1) [65] | Selumetinib + olaparib | Advanced solid tumours with RAS pathway alterations (n = 12) | ORR: 2/12 (17%) |
| BET inhibitor | Aftimos et al. (Phase 1b/2) [68] | ZEN-3694 + talazoparib | Metastatic triple-negative breast cancer without gBRCA1/2 mutations (n = 50) | ORR: 11/50 (22%) |
| Immunotherapy | Lee et al. (Phase 1) [83] | Durvalumab + olaparib | Recurrent or metastatic ovarian, breast, cervical, or endometrial cancer (n = 12) | ORR: 2/12 (17%) |
| Domchek et al, Bang et al., Thomas et al. (Phase 1/2 MEDIOLA) [84, 85, 91] | Durvalumab + olaparib | Advanced germline BRCA-mutated breast cancer and ovarian cancer; metastatic gastric cancer and relapsed SCLC (n = 88) | ORR: 4/39 (10%) in gastric cancer; 19/30 (63%) in gBRCA1/2-mutated breast cancer; 2/19 (11%) in SCLC | |
| Konstantinopoulos et al., Vinayak et al. (Phase 1/2 TOPACIO/KEYNOTE-162) [87, 92] | Niraparib + pembrolizumab | Recurrent platinum-resistant ovarian cancer and advanced TNBC (n = 115) | ORR: 10/60 (18%) in ovarian cancer; 10/55 (18%) in TNBC | |
| Reiss et al. (Phase 1b/2) [93] | Niraparib + ipilimumab or niraparib + nivolumab maintenance after platinum chemotherapy | Advanced platinum-sensitive pancreatic cancer (n = 91) | 6-month PFS: 21% with niraparib + nivolumab and 60% with niraparib + ipilimumab | |
| Friedlander et al. (Phase 1) [82] | Pamiparib + tislelizumab | Advanced solid tumours (n = 49) | ORR: 10/49 (20%) | |
| Yap et al. (Phase 1) [94] | Dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab | Advanced solid tumours (n = 35) | ORR: 4/22 (18.2%) with niraparib and 4/13 (30.8%) with niraparib + bevacizumab | |
| ATR inhibitor | Shah et al. (Phase 2) [102] | Ceralasertib + olaparib | Recurrent platinum-resistant, PARPi-naive ovarian cancer (n = 12) | ORR: 0/12 (0%) |
| Mahdi et al. (Phase 2) [147] | Ceralasertib + olaparib | Advanced solid tumours with deleterious germline or somatic alterations in HR genes (n = 25) | ORR: 2/25 (8.3%) | |
| CHK1 inhibitor | Do et al. (Phase 1) [148] | Prexasertib + olaparib | Advanced solid tumours, ovarian cancer with BRCA1/2 mutation. Previous PARPi allowed (n = 18) | ORR: 4/18 (22%) in patients with BRCA1/2-mutant, PARP inhibitor–resistant ovarian cancer |
| WEE1 inhibitor | Westin et al. (Phase 2) [111] | Adavosertib +/− olaparib | Recurrent ovarian, fallopian tube, or primary peritoneal cancer with documented progression on PARPi; 48% had germline or somatic BRCA1/2 mutation (n = 35) | ORR: 10/35 (29%) with adavosertib + olaparib vs 8/35 (23%) adavosertib |
| Yap et al. (Phase 1) [113] | Sequential adavosertib and olaparib | Advanced cancer with actionable DDR variants (n = 12) | ORR: 3/12 (25%) | |
| Antiandrogen | Clarke et al. (Phase 3) [123] | Abirateraone +/− olaparib | Metastatic castration-resistant prostate cancer (n = 796) | Radiographic PFS: 24.8 mo (abiraterone/olaparib) vs 16.6 mo (abiraterone) |
| Chi et al. (Phase 3) [124] | Abirateraone +/− niraparib | Metastatic castration-resistant prostate cancer (n = 423) | Radiographic PFS in HR-deficient mCRPC: 16.5 mo (abiraterone/niraparib) vs 13.7 mo (abiraterone) |
PFS progression-free survival, ORR overall response rate, TMZ temozolomide, mo months, chemo chemotherapy, gBRCA1/2 germline BRCA1 and BRCA2, SCLC small cell lung cancer, DDR DNA damage response, TNBC triple-negative breast cancer, HR homologous repair, PARPi PARP inhibitor, mCRPC metastatic castration-resistant prostate cancer.