Table 3 Phase II/III studies of PARP inhibitors in ovarian cancer
| Study | Patient population | BRCA status of patient population | Treatment arms | Total accrual | Primary endpoint | Results | ||
|---|---|---|---|---|---|---|---|---|
| Objective Response Rate (ORR) | Progression free survival (PFS) | Pertinent Findings | ||||||
| Audeh MW et al. Lancet. 2010 [4]. | Recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma | BRCA1/2 positive |
Cohort 1: Olaparib 400 mg BID Cohort 2: Olaparib 100 mg BID | 57 | ORR |
Cohort 1: 33% Cohort 2: 13% |
Cohort 1: 5.8 months Cohort 2: 1.9 months | Positive proof of concept of utility of PARP inhibitors from phase I data. Superior efficacy of 400 mg BID dosing. |
| Kaye SB et al. J Clin Oncol. 2012 [73]. | Platinum resistent recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma | BRCA1/2 positive |
Arm 1: Olaparib 200 mg BID Arm 2: Olaparib 400 mg BID Arm 3: PLD 50 mg/m2 | 97 | PFS |
Arm 1: 25% Arm 2: 31% Arm 3: 18% |
Arm 1: 6.5 months Arm 2: 8.8 months Arm 3: 7.1 months | No significant difference in outcomes between 2 doses of olaparib and PLD. |
| Gelmon KA et al. Lancet Oncol. 2011 [57]. | Advanced metastatic or recurrent ovarian, primary peritoneal or fallopian tube cancer (high-grade serous and/or undifferentiated) or breast cancer |
BRCA1/2 positive AND BRCA1/2 negative | Olaparib 400 mg BID | 91 (65 with gynecologic cancer) | ORR |
BRCA1/2 positive: 41% BRCA1/2 negative: 24% BRCA1/2 positive + platinum sensitive: 60% BRCA1/2 negative + platinum sensitive: 50% BRCA1/2 positive + platinum resistant: 33% BRCA1/2 negative + platinum resistant: 4% |
BRCA1/2 positive: 221 days BRCA1/2 negative: 192 days | Olaparib has activity in BRCA1/2 positive and negative populations. |
| Ledermann J et al. Lancet Oncol. 2014 [5]. | Platinum sensitive recurrent high grade serous epithelial ovarian, primary peritoneal, or fallopian tube carcinoma |
BRCA1/2 positive AND BRCA1/2 negative |
(Maintenance therapy following platinum-based chemotherapy) Arm 1: Olaparib 400 mg BID Arm 2: Placebo | 265 | PFS |
Arm 1: 8.4 months Arm 2: 4.8 months Olaparib + BRCA1/2 positive: 11.2 months Olaparib + BRCA1/2 negative: 5.6 months Placebo + BRCA1/2 positive: 4.3 months Placebo + BRCA1/2 negative: 5.5 months | Olaparib maintenance associated with improved PFS. No diffrence in OS. | |
| Oza AM et al. Lancet Oncol. 2015 [74]. | Platinum sensitive recurrent serous ovarian cancer |
BRCA1/2 positive AND BRCA1/2 negative |
Arm 1: Olaparib 200 mg BID + Paclitaxel 175 mg/m2 + Carboplatin AUC 4 × 6 cycles followed by olaparib 400 mg BID maintenance Arm 2: Paclitaxel 175 mg/m2 + Carboplatin AUC 4 × 6 cycles | 162 | PFS |
Arm 1: 64% Arm 2: 58% |
Arm 1: 12.2 months Arm 2: 9.6 months | Olaparib associated with improved PFS. |
| Coleman RL et al. Gynecol Oncol. 2015 [75]. | Recurrent or persistent ovarian, primary peritoneal or fallopian tube cancer | BRCA1/2 positive | Veliparib 400 mg BID | 52 | ORR |
Total population – 26% Platinum resistant – 20% Platinum sensitive – 35% BRCA1 – 26% BRCA2 – 27% | 8.11 months | Veliparib has single agent acitivity in platinum resistent disease. |
| Kaufman B et al. J Clin Oncol. 2015 [76]. | Platinum resistent recurrent ovarian, primary peritoneal or fallopian tube cancer | BRCA1/2 positive | Olaparib 400 mg BID | 193 | ORR | 31% | 225 days | Olaparib has single agent acitivity in BRCA1/2 positive platinum resistent disease. |
| Kummar S et al. Clin Cancer Res 2015 [58]. | Recurrent ovarian cancer or recurrent primary peritoneal, fallopian tube or high-grade serous ovarian cancers |
BRCA1/2 positive AND BRCA1/2 negative |
Arm 1: Cyclophosphamide 50 mg daily Arm 2: Cyclophosphamide 50 mg daily + Veliparib 60 mg daily | 75 | ORR |
Arm 1: (n = 38) 1 complete response, 6 partial responses Arm 2: (n = 37) 1 complete response, 3 partial responses |
Arm 1: 2.3 months Arm 2: 2.1 months | The addition of veliparib to cyclophosphamide did not improve the response rate or the median PFS. |
| Mirza MR et al. N Engl J Med 2016 [48]. | Platinum sensitive recurrent ovarian cancer or recurrent primary peritoneal, fallopian tube or high-grade serous ovarian cancers |
BRCA1/2 positive AND BRCA1/2 negative | Niraparib 300 mg daily vs. placebo daily | 553 | PFS |
gBRCA cohort - Niraparib: 21.0 months - Placebo: 5.5 months non-gBRCA with HRD cohort - Niraparib: 12.9 months - Placebo: 3.8 months non-gBRCA cohort - Niraparib: 9.3 months - Placebo: 3.9 months | Niraparib maintenance therapy has activity for platinum-sensitive recurrent ovaruan cancer regardles of the presence or absense of gBRCA mutations or HRD status. | |
| Swisher EM, et al. Lancet Oncol 2017 [59]. | Platinum sensitive recurrent ovarian cancer or recurrent primary peritoneal, fallopian tube or high-grade ovarian cancers |
BRCA1/2 positive AND BRCA1/2 negative | Rucaparib 600 mg BID | 206 | PFS |
BRCA 1/2 positive – 80% BRCA1/2 wild-type and LOH high – 29% BRCA1/2 wild-type and LOH low – 10% |
BRCA 1/2 positive: 12.8 months BRCA1/2 wild-type and LOH high: 5.7 months BRCA1/2 wild-type and LOH low: 5.2 months | Rucaparib acitivity in BRCA1/2 mutant and BRCA wild-type LOH high platinum sensitive recurrent disease. |