Table 2.
Antiangiogenic therapy plus PARP inhibitor clinical trials.
| Trial Name/NCT Number | Phase | Drugs | Eligible Patients | Dose/Schedule | Findings of Primary Endpoint(s) | Findings of Secondary Endpoint(s) | Notable common grade AEs (≥10%) |
|---|---|---|---|---|---|---|---|
| Completed antiangiogenic therapy + PARPi trials | |||||||
| PAOLA-I NCT02477644 Ray-Coquard I, et al. NEJM (2019). Martin AG, et al. Annals of Oncology (2020). Abstract. |
Randomized, double-blind phase III | Bevacizumab plus olaparib | Newly diagnosed advanced/high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, with complete or partial response to 1st line platinum-based chemotherapy (n = 806) | Bevacizumab 15 mg/kg IV q3w up to 15 mo plus olaparib 300 mg PO BID vs placebo up to 24 mo (n = 537 received o + b; n = 269p + b) |
Median PFS for all: 22.1 mo o + b vs. 16.6 mo p + b (HR = 0.59, 0.49–0.72, p < 0.001) HRD including BRCAm: 37.2 mo o + b vs. 17.7 mo p + b (HR = 0.33, 0.49–0.72, p < 0.001) HRD without BRCAm 28.1 mo o + b vs. 16.6 mo p+ b (HR = 0.43, 0.28–0.66 p < 0.001) |
Median PFS2 for all: o + b 36.5 mo vs. p + b 35.5 mo (HR = 0.78, 0.64–0.95, p= 0.0125) HRD including BRCAm: 50.3 mo o + b vs. 35.3 mo p + b HR = 0.56, 0.41–0.77, p < 0.001) HRD without BRCAm 50.3 mo o + b vs. 30.1 mo p + b (HR = 0.60, 0.38–0.96 p < 0.001) |
Hypertension (19%), anemia (17%) |
| NSGO-AVANOVA/ENGOT-ov24 Mirza MR, et al. Cancer Chemo & Pharmacology (2019). Mirza MR, et al. Lancet Oncology (2019). |
Randomized, open-label phase I/II | Bevacizumab plus niraparib | Platinum-sensitive recurrent high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer (n = 12 (phase I), n = 97 (phase II)) | Bevacizumab 15 mg/kg IV q3w plus niraparib 100–300 mg PO QD (n = 12) (phase I) Niraparib 300 mg PO QD with (n = 48) or without (n = 49) bevacizumab 15 mg/kg IV q3w (phase II) |
RP2D (phase I): bevacizumab 15 mg/kg IV q3w plus niraparib 300 mg PO QD Median PFS (phase II): 11.9 mo n + b vs. 5.5 mo niraparib alone (HR = 0.35, 0.21–0.57, p < 0.0001) |
Median PFS (phase I): 11.6 mo (8.4–20.1) Median OS (phase I): 25.3 mo (11.2-NA) ORR (phase I): 50% (21–79) ORR: 60% n + b vs. 27% niraparib alone (OR = 4.23, 1.79–9.97, p = 0.001) CBR (CR + PR + SD lasting ≥ 12 weeks): 79% n + b vs. 53% niraparib alone (OR = 3.36, 1.37–8.22, p = 0.008) |
Hypertension (42%), anemia (25%), thrombocytopenia (16%) (phase I) Hypertension (21%), anemia (15%), thrombocytopenia (10%) (phase II) |
| NRG-GY004 NCT02446600 Liu JF, et al. Journal of Clinical Oncology (2020). Abstract. |
Randomized, open-label phase III | Cediranib plus olaparib | Platinum-sensitive recurrent, high-grade ovarian, fallopian tube, or primary peritoneal cancer (n = 528) | Standard chemotherapy (paclitaxel/gemcitabine/doxorubicin plus carboplatin) (n = 166) vs. olaparib 300 mg PO BID (n = 183) vs. olaparib 200 mg PO BID plus cediranib 30 mg PO QD (n = 179) | Median PFS: 8.2 mo o vs. 10.4c + o vs. 10.3 mo SOC (HR = 0.856, 0.66–1.11, p = 0.08 for c + o vs. SOC; HR = 1.20, 0.93–1.54 for o vs. SOC) | ORR: 52.4% o, 69.4% c + o, 71.3% SOC | Hypertension (31.4%), gastrointestinal events (30.1%), fatigue (17.5%) (in the c + o arm) |
|
NCT01116648 Liu JF, et al.Lancet Oncology (2014). Liu JF, et al. Annals of Oncology (2019). |
Randomized, open-label phase II | Cediranib plus olaparib | Platinum-sensitive recurrent high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer (n = 90) | Olaparib 400 mg PO BID (n = 46) vs. olaparib 200 mg PO BID plus cediranib 30 mg PO QD (n = 44) | Median PFS: 16.5 mo c + o, 8.2 mo. o (HR = 0.50, 0.30–0.83, p = 0.006) |
ORR: 79.6% c +o vs. 47.8% o (OR = 4.24, 1.53–12.22, p = 0.002) Median OS: 44.2 mo. c + o vs. 33.3 mo. o (HR = 0.64, 0.36–1.11, p = 0.11) |
Hypertension (41%), fatigue (27%), diarrhea (23%) |
| EVOLVE NCT02681237 Lheurereux S, et al. Clinical Cancer Research (2020). |
Open-label, single-arm phase II | Olaparib plus cediranib after prior PARPi progression | Recurrent high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer (n = 34), divided into 3 cohorts: Platinum-sensitive after progression on PARPi (cohort 1) (n = 11) Platinum-resistant after progression on PARPi (cohort 2) (n = 10) Patients with progression on standard chemo after progression on PARPi (cohort 3) (n = 13) |
Olaparib 300 mg PO BID plus cediranib 20 mg PO QD |
ORR: 9% overall; 0% (cohort 1), 20% (cohort 2), 8% (cohort 3) Median 16-week PFS rate: 47% (33–67) overall; 55% (32–94) (cohort 1), 50% (27–93) (cohort 2), 39% (19–77) (cohort 3) |
DCR (CR + PR + SD): 68% overall; 82% (cohort 1), 60% (cohort 2), 62% (cohort 3) CA-125 response rate: 15% overall; 18% (cohort 1), 10% (cohort 2), 15% (cohort 3) 1-year OS: 82% (62–100) (cohort 1), 69% (46–100) (cohort 2), 40% (18–92) (cohort 3) |
Diarrhea (12%) Hypertension was observed in 24% of all patients (5.3% experienced grade 3/4) |
| CONCERTO NCT02889900 Lee JM, et al. Journal of Clinical Oncology (2020). Abstract. |
Open-label, single-arm phase II | Cediranib plus olaparib | Platinum-resistant, high-grade gBRCAwt epithelial ovarian, fallopian tube, or primary peritoneal cancer, with ≥ 4 prior lines of therapy (n = 60) | Cediranib 30 mg PO QD plus olaparib 200 mg PO BID | ORR by independent central review: 15.3% (7.2–27.0) |
Median duration of response: 8.3 mo (5.6–10.3) Median PFS: 5.1 mo (3.5–5.5) Median OS: 13.2 mo (9.4–16.4) |
Hypertension (30%), fatigue (22%), diarrhea (13%) |
| BAROCCO NCT03314740 Colombo N, et al. Annals of Oncology (2019). Abstract. |
Randomized, open-label phase II | Cediranib plus olaparib | Platinum-resistant recurrent high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer (n = 123) | Paclitaxel 80 mg/m2 IV qw (control) vs. cediranib 20 mg PO QD (continuous) plus olaparib 300 mg PO BID vs. cediranib 20 mg PO QD 5 days/week (intermittent) plus olaparib 300 mg PO BID | PFS: 3.1 mo (control), 5.7 mo (continuous) (HR = 0.76, 90% CI 0.49–1.17, p = 0.28), 3.8 mo (intermittent) (HR = 1.08, 90% CI 0.36–1.10, p = 0.76) | ORR, PFS2, OS, quality of life, toxicity | Farter details pending |
| Ongoing/incomplete antiangiogenic therapy + PARPi trials | |||||||
| ICON9 NCT03278717 Elyashiv O, et al. Int J Gynecol Cancer (2020). |
Randomized, open-label phase III | Maintenance cediranib plus olaparib | Platinum-sensitive recurrent high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer (n = 618) | Olaparib 300 mg PO BID plus cediranib 20 mg PO QD vs. olaparib 300 mg PO BID alone | PFS OS |
RR, PFS/OS from 2nd line chemotherapy, PFS per CA-125/GCIG criteria, TSST, quality of life (EORTC QLQ-c30 score) | Accrual ongoing |
| ETCTN9825 NCT02345265 Liu JF, et al. Journal of Clinical Oncology (2018). Abstract. |
A phase II biomarker single-arm study | Cediranib plus olaparib | Platinum-sensitive or platinum-resistant/refractory high-grade ovarian, fallopian tube, or primary peritoneal cancer (n = 70) | Cediranib 300 mg PO QD plus olaparib 200 mg PO BID | ORR: 77% (63–88) in platinum-sensitive cohort (n = 35), 20% (11–38) in platinum-resistant cohort (n = 35) | DCR (CR + PR + SD at 16 wks): 91% in platinum-sensitive cohort, 43% in platinum-resistant cohort | Completed enrollment Further biomarker details pending |
| OCTOVA NCT03117933 |
Randomized, open-label phase II | Cediranib plus olaparib | Platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer | Paclitaxel 80 mg/m2 IV qw vs. olaparib 300 mg PO BID vs. olaparib PO BID plus cediranib 20 mg PO QD | PFS | OS, ORR, quality of life (EORTC QLQ-c30 score), safety & tolerability | Completed enrollment |
| NRG-GY005 NCT02502266 |
Randomized, open-label phase II/III | Cediranib plus olaparib | Platinum-resistant/refractory ovarian, fallopian tube, or primary peritoneal cancer | Standard chemotherapy (paclitaxel, doxorubicin, topotecan) (arm 1) vs. cediranib PO QD plus olaparib PO BID (arm 2) vs. cediranib PO (arm 3) | ORR (phase II) PFS (phases II & III) OS (phase III co-primary) |
ORR (phase III) | Completed enrollment |
*
All reported ranges are 95% CI unless otherwise stated
Abbreviations: AE: adverse event; BID: twice daily; CBR: clinical benefit rate; CR: complete response; DCR: disease control rate; EORTC QLQ-c30: European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30; HR: hazards ratio; NA: not applicable; OR: odds ratio; ORR: objective response rate; OS: overall survival; PARP: poly (ADP-ribose) polymerase; PARPi: poly (ADP-ribose) polymerase inhibitor; PFS2: second progression-free survival; PFS: progression-free survival; PO: by mouth; PR: partial response; QD: once daily; RP2D: recommended phase 2 dose; SD: stable disease; SOC: standard of care; TSST: time to second subsequent therapy; c + o: cediranib plus olaparib; mo: months; n + b: niraparib plus bevacizumab; o + b: olaparib plus bevacizumab; o: olaparib; p + b: placebo plus bevacizumab; q3w: once every 3 weeks; qw: once weekly; HRD: homologous recombination deficiency; BRCAm: BRCA mutation; gBRCAwt germline BRCA wild type