Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy

ObjectivesThough it is known to all that PARP inhibitors (PARPis) are effective when used as maintenance alone for women with recurrent ovarian cancer (ROC), little is known about whether using them in combination with other drugs would contribute to a better efficacy. We performed a systematic review and meta-analysis to explore the efficacy and safety of PARPi combination therapy compared with monotherapy.Materials and MethodsWe searched for randomized controlled trials (RCTs) that offered the date we needed in PubMed, Embase, Cochrane, and major conference. Data extraction and processing were completed by three investigators to compare OS, PFS, and ORR both in intervention and in control subset. Then, we calculated the pooled RR and 95% CI of all-grade and high-grade adverse effects to study its safety. And we evaluated the within-study heterogeneity by using subgroup and sensitivity analysis.Results and ConclusionA total of three eligible RCTs covering 343 women were included. In PFS analysis, PARP inhibitor (PARPi) combination therapy can significantly improve PFS for women with ROC when compared with the controls (HR: 0.46, 95% CI: 0.35 to 0.59), especially for those with mutated BRCA (HR: 0.29, 95% CI: 0.19 to 0.45). And in OS analysis, combination therapy is not inferior to monotherapy (HR: 0.90, 95% CI: 0.50 to 1.61). As for ORR, the effectiveness of combination therapy and monotherapy was almost the same (RR: 1.04, 95% CI: 0.82 to 1.31). Additionally, combination therapy seldom causes more adverse events, both in all-grade and in high grade.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, International Prospective Register of Systematic Reviews (PROSPERO) (identifier, CRD42018109933).

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A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.18_suppl.lba5500 ◽

2014 ◽

Vol 32 (18_suppl) ◽

pp. LBA5500-LBA5500 ◽

Cited By ~ 8

Author(s):

Joyce Liu ◽

William Thomas Barry ◽

Michael J. Birrer ◽

Jung-min Lee ◽

Ronald J. Buckanovich ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase 1 ◽

Parp Inhibitor ◽

Objective Response ◽

Progression Free Survival ◽

Recurrent Ovarian Cancer ◽

Parp Inhibitors ◽

Open Label ◽

Angiogenic Therapy ◽

Platinum Sensitive

LBA5500 Background: PARP inhibitors and anti-angiogenics are clinically active in recurrent ovarian cancer (OvCa). Preclinical studies suggest these agents can synergize, and a phase 1 study showed that the combination of cediranib (ced) and olaparib (olap) is well-tolerated. We therefore compared the activity of olap alone (Olap) to combined ced and olap (Ced/Olap) in treatment of recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related OvCa (NCT 01116648). Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. Progression-free survival (PFS) was defined as time from randomization to radiographic progression or death. With a target N=90 pts, the study was powered to detect a hazard ratio (HR) of 1.75 (median PFS 6 vs 10.5 mo). Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). At a planned interim analysis the DSMB recommended release of data. As of Jan 7, 2014, 41 pts had a PFS event. Median PFS was 9.0 mos for Olap and 17.7 mos for Ced/Olap (HR 2.9, 95% CI 1.5-5.6, p = 0.001). There were 2 complete responses (CR) and 21 partial responses (PR) in pts on Olap (56% objective response rate, ORR) and 3 CRs and 33 PRs in pts on Ced/Olap (84% ORR, p = 0.008). The overall rate of Gr3/4 toxicity was higher for pts on Ced/Olap (70%) than on Olap (7%). Differentially occurring toxicities included fatigue (27% Ced/Olap vs 7% Olap), diarrhea (23% vs 0%), and hypertension (39% vs 0%). Updated efficacy and exploratory subgroup analyses will be presented. Conclusions: Combined Ced/Olap significantly extended PFS and ORR compared to Olap in plat-sens OvCa. Further studies of this oral combination in plat-sens OvCa are warranted. Clinical trial information: NCT01116648.

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Combination of PARP and ATR inhibitors (olaparib and ceralasertib) shows clinical activity in acquired PARP inhibitor-resistant recurrent ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5516 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5516-5516

Author(s):

Stephanie L. Wethington ◽

Payal D Shah ◽

Lainie P. Martin ◽

Janos Laszlo Tanyi ◽

Nawar A. Latif ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Trial ◽

Kinase Inhibitors ◽

Parp Inhibitor ◽

Objective Response ◽

Clinical Trial Design ◽

Recurrent Ovarian Cancer ◽

Ca 125 ◽

Clinical Activity ◽

Brca Mutations

5516 Background: Following multiple blockbuster studies demonstrating long-term progression free and overall survival benefits with poly(ADP-ribose)polymerase inhibitors (PARPi), they have become an integral component of high grade serous ovarian cancer (HGSOC) treatment. Unfortunately, tumors ultimately acquire resistance and thus therapies that overcome PARPi-resistance are urgently needed. Preclinical studies show the addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARPi overcome PARPi-resistance. We present results of an investigator-initiated study of the combination PARPi (olaparib) and ATRi (ceralasertib) in patients who were on a PARPi and experienced disease progression. Methods: We conducted a non-randomized trial (NCT03462342) in platinum sensitive HGSOC immediately following prior PARPi treatment of a 28 day cycle of olaparib 300mg orally twice daily and ceralasertib 160mg orally once daily on days 1-7. Eligibility required a germline or somatic BRCA1/2 mutation, other homologous recombination deficient (HRD) mutation, or positive HRD score (>42 on Myriad My Choice). Clinical benefit from prior PARPi was required ( > 12 months on treatment for 1st line maintenance, > 6 months for ≥2nd line maintenance, or treatment of recurrence with response by CA-125 or imaging). No intervening treatment between the PARPi and enrollment was permitted. The primary objectives were safety and objective response rate (ORR). Results: Thirteen patients (pt) of median age 60 years (range 43-78) were enrolled. 9 pt (69%) had germline BRCA mutations, 3 (23%) somatic BRCA mutations and 1 (8%) a positive HRD score. Median time on prior PARPi was 13 months (range 4-60). Prior PARPi indication was 1st line maintenance in 8% (n = 1), 2nd line maintenance in 38% (n = 5) and recurrence in 54% (n = 7). Nine pt (69%) had received olaparib prior to enrollment. The time from prior PARPi to cycle 1, day 1 was 34 days (range 22-311). The ORR was 46% (n = 6); all 6 demonstrating a PR. Pt received a median of 8 (range 3-23) cycles of olaparib and ceralasertib. 4 pt remain on study (4-14 months). 4 pt (31%) experienced grade 3 toxicity: 23% (n = 3) thrombocytopenia, 16% (n = 2) anemia, and 16% (n = 2) neutropenia. There were no grade 4/5 toxicities. There were 4 dose reductions (3 olaparib, 1 ceralasertib). No pt discontinued treatment due to toxicity. Conclusions: The combination of olaparib and ceralasertib is well tolerated and shows clinical activity in in a cohort of patients with recurrent HRD HGSOC who have progressed on prior PARPi thus warranting further investigation. This study is the first to suggest the potential of ATR inhibitors to overcome PARPi resistance in an HRD patient population. Molecular profiling studies are underway to identify potential biomarkers associated with response to guide future clinical trial design. Clinical trial information: NCT03462342.

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