Table 1.
Current PARP inhibitors under clinical development.
| Agent | # Potency for PARP Trapping | Mono Therapy Dose | Toxicities * | FDA Approvals ∫ | |
|---|---|---|---|---|---|
| Any (%) | Grade >/3 (%) | ||||
| Olaparib | ++ | 300 mg PO BID | Any 96% Fatigue 60% Nausea 45% Anemia 27% Abd pain 29% Diarrhea 29% Anorexia 25% Constipation 23% |
Any 40% Fatigue 5% Anemia 11% Abd pain 2% Anorexia 3Vomiting 1% Arthralgia 1% |
-2014: gBRCA mutation positive ovarian cancer in 4th line of therapy. ORR of 34%, PFS of 6.7 mo [56] -2017: Maintenance post-recurrence in ovarian, primary peritoneal or fallopian tube carcinoma with CR or PR after platinum-based chemotherapy irrespective of BRCA status. PFS: olaparib (19 mo) vs. placebo (5.5 mo), HR 0.3, p < 0.0001) [57,58] -2018: Front-line maintenance in gBRCA or sBRCA mutation positive ovarian or primary peritoneal or fallopian tube carcinoma with CR or PR after platinum-based chemotherapy. 3-yr OS: olaparib (84%) vs placebo (80%), HR 0.95 (95% CI 0.6–1.53) [59] -2018: gBRCA mutation positive, Her-2 negative metastatic breast cancer </2 lines of therapy. PFS: olaparib (7 mo) vs std Rx (4 mo), HR 0.58 (p < 0.001); OS: olaparib (19.3 mo) vs. standard therapy (19.6mo), HR 0.9 (p = 0.57) [60] |
| Rucaparib | ++ | 600 mg PO BID | Any 100% Nausea 75% Fatigue 69% Dysgeusia 39% Anemia 37% Constipation, Vomiting 37% Transaminitis 34% Diarrhea 32% Abd pain 30% Thrombocytopenia 28% |
Any 48% Anemia 18% Asthenia 7% Neutropenia 5% Thrombocytopenia 3% Transaminitis 10% Nausea, Vomiting 4% Abd pain, Diarrhea, Anorexia, Arthralgia 1% |
-2016: gBRCA or sBRCA mutation positive ovarian cancer after >/2 lines of therapy. PFS: BRCA mutation positive (13 mo), LOH high (6 mo), LOH low (5.2mo) [61,62] -2018: Maintenance post-recurrence in ovarian or primary peritoneal or fallopian tube carcinoma with CR or PR after platinum-based chemotherapy PFS: rucaparib (17mo) vs placebo (5 mo), HR 0.23 (p < 0.0001) [63] |
| Veliparib | + | 400 mg PO BID | Nausea 43% Vomiting 29% Anemia 24% Leukopenia 20% Thrombocytopenia 9% |
||
| Niraparib | +++ | 300 mg PO QD | Nausea 74% Thrombocytopenia 61% Fatigue 59% Anemia 50% Constipation 40% Vomiting 34% Neutropenia 30% Headache 26% Anorexia 25% Insomnia 24% Abd pain 23% |
Thrombocytopenia 34% Anemia 25% Neutropenia 20% Fatigue 8% Nausea 3% Hypertension 8% Vomiting 2% Abd pain, Dyspnea 1% |
-2017: Maintenance post-recurrence in ovarian or primary peritoneal or fallopian tube carcinoma with CR or PR after platinum-based chemotherapy. PFS: niraparib (21mo) vs placebo (5.5 mo), HR 0.27 (95% CI 0.17–0.41) [64] |
| Talazoparib | ++++ | 1 mg PO QD | Anemia 53% Fatigue 50% Nausea 49% Headache 32% Neutropenia 35% Thrombocytopenia 27% Vomiting 25% |
Anemia 39% Neutropenia 18% Thrombocytopenia 11% Leukopenia 6% Lymphopenia 3% Fatigue, Headache, Vomiting, back pain, dyspnea 2% |
-2018: gBRCA mutation, Her-2 negative metastatic breast cancer </3 lines of therapy. PFS: talazoparib (8.6mo) vs placebo (5.6 mo), HR 0.54; p < 0.001. Interim OS HR 0.76 (95% CI 0.55–1.06, p = 0.11) [65] |
| Pamiparib | 60 mg PO BID | Nausea 50% Fatigue 33% Anemia 20% Vomiting 15% Neutropenia 13% |
Anemia 13% Neutropenia 8% Fatigue 5% |
No FDA approved indications yet | |
# Relative PARP Trapping potency; +++ indicates the most potent, + indicates the least potent. ∫ As of 10th October 2019; * Olaparib based on Phase III POLO trial [66], Rucaparib based on Phase III ARIEL III [63], Niraparib based on Phase III NOVA trial [64], Talazoparib based on EMBRACA trial [65], Veliparib based on a Phase II trial [67], Pamiparib-Immature data from Phase I NCT 02361723 [55], Ongoing Phase III Pamiparib studies- NCT03519230, NCT03427814. Abbreviations: PARP = poly(ADP-ribose)polymerase; g = germline; s = somatic; m = mutant; CR = complete remission; PR = partial remission; Her-2 = Human epidermal growth factor receptor-2; Abd = abdominal; PFS = median progression free survival; OS= median overall survival.