Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study

Abstract

Background Olaparib is an oral poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic with activity against VEGFR-1, 2, and 3. Both agents have antitumor activity in women with recurrent ovarian cancer, and the combination of these agents was active and had manageable toxicities in a Phase 1 trial. We asked whether the combination of cediranib and olaparib could improve progression-free survival compared to olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. Methods We conducted a randomized, open-label, phase 2 study to evaluate the activity of olaparib monotherapy compared with combination cediranib and olaparib in women with ovarian cancer with measurable platinum-sensitive, relapsed, high-grade serous or endometrioid disease or those with deleterious germline BRCA1/2 mutations (gBRCAm). Patients were randomized using permuted blocks within stratum defined by gBRCA status and prior anti-angiogenic therapy to receive olaparib capsules 400mg twice daily or the combination at the recommended phase 2 dose of cediranib 30mg daily and olaparib capsules 200mg twice daily. The primary endpoint was progression-free survival (PFS) analyzed under intention to treat. The trial is registered with ClinicalTrials.gov, NCT01116648. The Phase 2 portion of the trial reported here is no longer accruing patients. Findings Forty-six of 90 randomized patients received olaparib alone, and 44 received cediranib/olaparib. Median PFS was significantly longer with cediranib/olaparib (17.7 vs. 9.0 mos, HR 0.42; p = 0.005). Grade 3 and 4 adverse events were more common with cediranib/olaparib, including fatigue (12 vs. 5), diarrhea (10 vs. 0), and hypertension (18 vs. 0). Subset analysis within stratum defined by BRCA1/2 status demonstrated activity of cediranib/olaparib in both gBRCAm and gBRCAwt/u (wild-type/unknown) patients. Significant improvement in PFS occurred in gBRCAwt/u women receiving cediranib/olaparib (16.5 vs. 5.7 mos, p = 0.008) with a smaller trend towards increased PFS in gBRCAm patients (19.4 vs. 16.5 mos, p = 0.16). Interpretation The combination of cediranib and olaparib significantly extended PFS by 8.7 months compared to olaparib alone in recurrent platinum-sensitive ovarian cancer. The activity observed with this oral combinaton in both gBRCAmt and gBRCAwt/u patients is encouraging and should be further explored as a potential alternative to cytotoxic chemotherapy. Given the side effect profile, such explorations should include assessments on quality of life and patient-reported outcomes to understand the effects of an ongoing oral regimen to that of intermittent chemotherapy.

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

“…However, the BRCA mutation status of the tumour was unknown in half of the patients in that subgroup (11 of 22 patients). 34 Additionally, we are not aware of any studies that have prospectively investigated progression-free survival or objective responses following platinum therapy in patients with relapsed, BRCA wildtype ovarian carcinoma, which makes it diffi cult to compare the results from ARIEL2 Part 1 with an expected frequency of response to platinum therapy.…”

Systemic Therapy for Recurrent Epithelial Ovarian Cancer: A Clinical Practice Guideline

“…Six of the included studies were assessments of olaparib in populations of women with serous tumour h i stolog ies 12,22,25,26,29,37 . Five st ud ies con sidered systemic treatment in patients with recurrent ovarian cancer 16,21,32,33,35 .…”

Molecular Chemotherapies in Gynecologic

“…Since then, bevacizumab has become a mainstay of both ovarian and cervical cancer treatment. A second VEGF-inhibitor, cediranib, has also shown promise; results from a phase II clinical trial show that the combination of cediranib with the PARP inhibitor olaparib is significantly more effective against recurrent platinum-sensitive ovarian cancer with BRCA mutations than olaparib alone (PFS of 17.7 vs. 9 months) [8]. VEGF inhibitors are not without side effects, however, including hypertension, fatigue, bleeding (particularly nosebleeds), headache, rash, and bowel perforation and fistula formation in up to 3% of patients [9].…”