Evolve: A post PARP inhibitor clinical translational phase II trial of cediranib-olaparib in ovarian cancer—A Princess Margaret Consortium – GCIG Phase II Trial.

Abstract

5521 Background: PARP inhibitors (PARPi) are approved therapies in high grade serous ovarian cancer (HGSOC). There are few studies after PARPi progression and correlation with dynamic changes in resistance. We hypothesized that PARPi resistance could be overcome by adding an anti-angiogenic. Methods: We report the first phase 2 trial assessing the combination of olaparib and cediranib after PARPi failure in HGSOC. This investigator initiated study included three cohorts of 10 evaluable patients (pts): i) platinum sensitive post PARPi (PS), ii) platinum resistant post PARPi (PR) and iii) exploratory cohort of pts re-challenged with chemotherapy post PARPi progression (PE) (NCT02681237). The primary objective was to determine objective response rate by RECIST v1.1 and progression free survival (PFS) at 16 weeks. Secondary objectives were to evaluate safety, PFS, overall survival (OS) and mechanisms of PARPi resistance. Pts who had radiographic progression on any PARPi were eligible. Archival tumor at initial diagnosis and baseline tumor biopsy at PARPi progression were mandatory. Pts received olaparib tablets 150mg BID with cediranib 20mg QD until progression or unacceptable toxicity. CT scans were performed every 8 weeks. Whole exome and RNA sequencing were performed on paired tumors tissues. Results: Thirty-four pts were enrolled. BRCA1/2 mutations were found in 9/11 PS, 8/10 PR and 7/13 PE pts. By RECIST1.1, four partial responses were observed (2 in PR and 2 in PE cohorts) and 18 stable disease. The 16−week PFS was 54.5% (31.8−93.6) in PS, 50% (26.9−92.9) in PR and 36% (15.6−82.8) in PE, respectively. OS at 1 year was 81.8% (61.9−100) in PS, 64.8% (39.3−100) in PR and 39.1% (14.7−100) in PE. Main related adverse events were anemia, hypertension, diarrhea and fatigue, grade 3 < 10%. Molecular analyses identified different mechanisms of PARPi resistance in ~77% of evaluable pts with matched pre-post PARPi progression biopsies such as reversion mutations in BRCA1/2 and other homologous repair (HR) genes; BRCA, HR and MDR upregulation, CCNE amplification and RIG-I like receptor downregulation. Conclusions: Treatment with olaparib-cediranib after PARPi failure was feasible and met the predefined bar for efficacy in each cohort. This is the largest clinical trial prospectively evaluating PARPi failure and correlating tissue genomic mechanisms of resistance. Clinical trial information: NCT02681237.

Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

“…OS at one year was 81.8% (61.9-100) in PS, 64.8% (39.3-100) in PR and 39.1% (14.7-100) in PE. Correlative analyses identified mechanisms of PARPi resistance in~77% of evaluable patients with matched pre-post PARP inhibitor progression biopsies, such as reversion mutations in BRCA1/2 and other HR genes, MDR1 upregulation, CCNE amplification and RIG-I like receptor downregulation [113]. The anti-tumour activity of this combination will be assessed further in the OVC2 trial (NCT02502266), a randomised phase III study evaluating Olaparib+Cediranib vs. chemotherapy in Platinum Resistant OC.…”

Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events

“…Our group assessed the combination of olaparib (300 mg, tablets twice daily) and cediranib (20 mg once daily) in a single-arm phase II study in patients having progressed to prior PARPi treatment, regardless of platinum sensitivity, and showed a signal of activity. 37 Treatment-related grade ≥3 adverse events were 38% in this case, mainly diarrhea, followed by anemia; the difference in drug dosing between the two studies might explain the numerical difference in adverse events' severity and frequency. Another phase II study in platinum-sensitive recurrence cells/L, a starting dose of 200 mg daily is recommended.…”

“…Our group assessed the combination of olaparib (300 mg, tablets twice daily) and cediranib (20 mg once daily) in a single-arm phase II study in patients having progressed to prior PARPi treatment, regardless of platinum sensitivity, and showed a signal of activity. 37 Treatment-related grade ≥3 adverse events were 38% in this case, mainly diarrhea, followed by anemia; the difference in drug dosing between the two studies might explain the numerical difference in adverse events’ severity and frequency. Another phase II study in platinum-sensitive recurrence (patients with front-line bevacizumab and/or PARPi also included) assessed niraparib versus niraparib (300 mg, once daily) and bevacizumab (15 mg/kg, every 3 weeks) as a treatment strategy; showing a significant improvement in progression-free survival in the intention-to-treat population (irrespective of HRD), as well as in the pre-specified non-germline BRCA m carrier subgroup, but not in BRCA m carriers.…”

“…A recent phase II study assessed the combination of PARPi and anti-angiogenics in the post-PARP setting. 37 In the precision medicine era, assessment of the mechanism of resistance to PARPi on an individual patient basis may unravel the best treatment strategy and, ultimately, potential PARPi combinations.…”

PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

“…Therefore, preclinical data suggest that combining anti-angiogenic agents with PARPi may be effective in PARPi resistant disease. A single arm phase II trial treated 34 patients with PARPi-resistant EOC with olaparib and cediranib (oral anti-angiogenic), yielding 4 patients who achieved partial responses and 18 patients with stable disease [116]. That this combination was effective even in PARPi-resistant cases may be due to cediranib-mediated suppression of BRCA1/2 and RAD51 expression, both indirectly through induction of hypoxia, and directly through transcriptional repression [117].…”