Table 2.
Trial results PARP inhibitors in pancreatic cancer
| Clinical Study | Phase | Patient Population | Intervention | Outcome | ADEs |
|---|---|---|---|---|---|
| PARPi as Monotherapy | |||||
|
NCT01078662 Kauffman et al. [56] |
II | gBRCA1/2 mutation positive advanced recurrent cancers, PDAC cohort with progression on gemcitabine (65% prior platinum-based regimen) | Single arm olaparib 400mg PO BID |
PEP: ORR (PDAC cohort) 22% SEP: Stable disease at > 8 weeks 35%, DOR 134 days, PFS 4.6 mo, OS 9.8 mo |
Any grade: Fatigue (74%), Nausea (48%), Vomiting, Anemia (40%) Grade >/3: Anemia (17%) Fatigue (13%) |
|
NCT02042378 Shroff et al. [70] |
II | sBRCA1/2 or gBRCA1/2 mutation positive advanced PDAC, 1–2 prior lines of therapy, prior platinum exposure in 79% pts, platinum refractory disease in 42% patients | Single arm rucaparib 600 mg BID |
PEP: ORR 16% (3/19, 1CR and 2PR), SEP: DCR 32%, 44% with 1 prior line of therapy |
Any grade: Nausea (63%) Anemia (47%), Abdominal pain, fatigue (37%) Grade >/3: Anemia (32%) Fatigue, Ascites (16%) Nausea, abdominal pain, increased AST, ALT (10%) |
| Lowery et al. [71] | II | gBRCA1/2 or PALB2 mutation positive advanced PDAC patients, prior 1–2 lines of therapies (88% prior platinum-based regimen, 64% of these pts had PD on platinum-based regimen) | Single arm veliparib 300mg BID PO (n = 3), 400 mg BID (n = 15) |
PEP: ORR-No CR or PR, Stable disease 25% pts at 8 weeks SEP: PFS 1.7 mo, OS 3.1 mo |
Fatigue (25%) Elevated bilirubin (19%) Thrombocytopenia, dehydration, increased alkaline phosphatase (13%) |
|
NCT02677038, NCT02511223 Golan et al. [72] |
II | Advanced PDAC, >/1 lines of therapy with BRCAness phenotype | Single arm olaparib PO BID |
PEP: ORR Israel-5SD, 12 PD; U.S.-2PR, 6 SD, 3 PD SEP: PFS-14 wks (Israel) and 25 wks (U.S.) |
Grade 1–2 anemia, fatigue, nausea |
| PARPi as Maintenance Therapy | |||||
| NCT02184195, Golan et al. [66] | III | gBRCA1/2 mutation positive, mPDAC, non-progressive disease during first line platinum-based therapy for at least 16 weeks | 3:2 randomization to olaparib versus placebo |
PEP: PFS-7.4 mo vs 3.8 mo (HR 0.53, p = 0.004) SEP: OS (46% data maturity)-19 mo vs. 18 mo (p = 0.7), no difference in HrQOL scores |
Any grade: Olaparib vs. placebo (96% vs. 93%), Fatigue (60% vs. 35%), nausea (45% vs. 23%), abdominal pain (29% vs. 25%), anemia (27% vs. 17%) Grade >/3: Olaparib vs placebo (40% vs. 23%) Anemia (11% vs. 3%) Fatigue (5% vs. 2%) Abdominal pain (2% each) |
| NCT 03140670, Binder et al. [73] | II | gBRCA1/2, gPALB2, sBRCA1/2, or sPALB2 mutation positive advanced PDAC, non-progressive disease during first line platinum-based therapy for at least 16 weeks | Single arm rucaparib 600mg PO BID |
PEP: PFS Prelim data (19/24 pts enrolled, 42 planned) -mPFS of 9 mo SEP: ORR 37% (1CR, 6 PRs), DCR-90% for at least 8 weeks |
Most common (grade 1,2): Nausea (46%) Dysgeusia (33%) Fatigue (25%) No grade 3 ADEs |
| PARP in combination with chemotherapy | |||||
| NCT02890355, Chiorean et al. [74] | II | mPDAC, second line therapy with (1st line Rx with non-irinotecan-based therapy), 9% (11/123) pts with HRD (4 germline BRCA1/2, ATM; 7 somatic BCRA2, PALB2, ATM, CDK12), 20% (24/123) pts with DDR, non HRD mutations | 1:1 randomization to either veliparib + FOLFIRI vs FOLFIRI alone | Planned interim futility analysis at 35% PFS events PEP: OS 5.1 vs. 5.9 mo (HR 1.3, p = 0.2) SEP: PFS 2 mo vs. 3 mo (HR 1.5, p = 0.05) |
Most common Grade >/3 ADEs: Veliparib + mFOLFIRI vs FOLFIRI Neutropenia (33% vs. 20%) Fatigue (19% vs. 4%) Nausea (11% vs. 4%) |
| NCT01489865, Pishvaian et al. [75] | I/II | mPDAC pts, phase I (31 pts), phase II (33pts). Phase II pts preselected for germline or somatic BRCA1/2, PALB2 mutations (27%) or FH of breast /ovarian syndrome (69%); both previously treated (18/33) and untreated (15/33) | Veliparib + mFOLFOX6 | 57/64 pts evaluable PEP: ORR-26% all pts, 58% in pts with +FH, +DDR, platinum naïve (12 pts) SEP: OS 8.5 mo, PFS 3.7 mo |
Grade >/3: Myelosuppression (16%) Nausea, vomiting (6%) |
Abbreviations: g = germline; s = somatic; mPDAC = metastatic pancreatic ductal adenocarcinoma; PEP = primary end point; SEP = secondary end point; ORR = overall response rate; CR = complete response; PR = partial response; PFS = progression free survival; OS = overall survival; DOR = duration of response; DCR = disease control rate; mo = months; ADE = adverse drug-related events; FOLFIRI = FOLinic Acid+ 5-Fluorouracil+ IRInotecan; FOLFOX = FOLinic acid+ 5-Fluorouracil + Oxaliplatin; FH = family history; DDR = defective DNA damage repair; abd = abdominal; PO = per os; PARP = poly(ADP-ribose) polymerase.