Background

In the PAOLA-1/ENGOT-ov25 trial, adding maintenance ola to bev improved progression-free survival in homologous recombination deficiency-positive (HRD+; tumour BRCA1/2 mutation [tBRCAm] and/or genomic instability) pts with newly diagnosed AOC at higher and lower risk of progression by disease stage and surgical status. Greatest benefits were seen in lower-risk pts (Harter et al. Gynecol Oncol 2022). Here, we analysed 5-y OS according to clinical risk and HRD status.

Methods

Pts in response after first-line platinum-based chemotherapy + bev were randomized 2:1 to ola (300 mg bid; up to 24 months [mo]) + bev (15 mg/kg q3w; up to 15 mo) or placebo [pbo] + bev. This post hoc exploratory analysis evaluated OS in pts classified as higher risk (stage III with upfront surgery and residual disease or neoadjuvant chemotherapy; stage IV) or lower risk (stage III with upfront surgery and no residual disease), and by HRD status.

Results

537 pts were randomized to ola + bev and 269 to pbo + bev (median OS follow-up 61.7 and 61.9 mo, respectively). Of 806 randomized pts, 595 (74%) were classified as higher risk and 211 (26%) as lower risk. At final data cutoff (22 March 2022), OS events had occurred in 377 higher-risk pts (data maturity 63%) and 69 lower-risk pts (data maturity 33%). OS was prolonged with ola + bev in higher- and lower-risk pts with a tBRCAm or who were HRD+ (Table). No OS benefit was seen in HRD− pts in any clinical risk subgroup (Table). Subsequent PARP inhibitor therapy was received by 19.5% and 19.6% of ola + bev pts, and 45.9% and 45.2% of pbo + bev pts, in higher- and lower-risk groups, respectively.

Conclusions

This post hoc analysis of 5-y OS suggests that adding maintenance ola to bev should be considered for all HRD+ pts with newly diagnosed AOC, irrespective of their clinical risk status. Particular benefit was observed in HRD+ lower-risk pts who achieved 5-y OS rates of 88.3%.

Clinical trial identification

NCT02477644

Editorial acknowledgement

Medical writing assistance was provided by Helen Speedy, PhD, at Seques, funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Background

Niraparib (nir) showed a blinded independent central review–assessed PFS benefit as a first-line (1L) maintenance therapy (MT) in the primary analysis of PRIMA (data cut 17 May 2019) across biomarker subgroups, including a substantial benefit in patients (pts) with homologous recombination–deficient (HRd) tumours. These results were the basis for approval of nir as MT after response to 1L platinum-based chemotherapy (CT). Here we report investigator-assessed (IA) cPFS (the probability of remaining alive and progression free beyond a specified landmark) in PRIMA.

Methods

This double-blind, placebo (PBO)-controlled phase 3 trial evaluated nir in pts with newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer (OC) at high risk for relapse after a complete or partial response (CR or PR) to 1L platinum-based CT. Stratification factors were best response to 1L CT regimen (CR/PR), receipt of neoadjuvant CT (yes/no), and homologous recombination deficiency status (HRd or HRp/HRnd) per the Myriad myChoice® CDx PLUS assay. Pts received nir or PBO once daily (2:1 ratio). IA cPFS was analysed for the HRd and intention-to-treat (ITT) populations, using the 17 Nov 2021 data cut.

Results

The median follow-up time was 3.5 y. The estimated PFS rate at 4 y was 38% for nir-treated pts and 17% for PBO-treated pts in the HRd population and 24% (nir) vs 14% (PBO) in the ITT population. The 2-y cPFS probabilities beyond the 1- and 2-y landmarks were higher in the nir arm than in the PBO arm (HRd: 1 y: 62% vs 50%, 2 y: 74% vs 60%; ITT: 1 y: 54% vs 46%, 2 y: 67% vs 64%; Table).

Safety was previously reported (González-Martín, et al. Ann Oncol. 2022;33[suppl 7]:S789).

Conclusions

A durable PFS benefit (nir vs PBO) was observed up to 4 y after randomisation in the ITT and HRd populations, as determined by IA. Pts free from disease progression or death at the 2-y landmark had a high probability of remaining free from progression or death at 4 y, supporting the use of nir as a 1L MT.

Clinical trial identification

NCT02655016

Editorial acknowledgement

Writing and editorial support, funded by GSK (Waltham, MA, USA) and coordinated by Pru Roaf of GSK, was provided by Betsy C. Taylor, PhD, CMPP, Tafara T.R. Kunota, PhD, and Dena McWain of Ashfield MedComms, an Inizio company (Middletown, CT, USA).

Background

Clinical outcomes for rare subtypes of relapsed gynaecological cancers (GC) including ovarian clear cell carcinomas (CCC) and carcinosarcomas (CS) are poor with limited treatment options. Preclinical data demonstrate GC with deleterious ARID1A mutations (and thus ARID1A-protein loss) display increased sensitivity to ATR inhibition. In the absence of ARID1A mutations, ATR inhibitor sensitivity can be enhanced by combination with PARP inhibitors. ATARI is an academic, international, parallel cohort platform phase II trial assessing ceralasertib (CERA) in ARID1A stratified GC.

Methods

Relapsed CCC (ovarian OCCC/endometrial ECCC) patients (pts) with ARID1A loss received CERA alone (160 mg BD day (D) 1-14 of 28D cycle) (Cohort 1A); CCC with ARID1A no loss (Cohort 2) and other non-CCC histological subtypes (endometrioid, CS, cervical) CERA (160 mg OD D1-7) and olaparib (300 mg BD, D1-28) (Cohort 3). Primary endpoint is best overall objective response rate (ORR, RECIST v1.1); key secondary endpoints include disease control rate (DCR) and progression free survival (PFS). Each cohort recruited 29 pts under a Simon 2-stage design (p0=0.1, p1=0.3, alpha=5%, power=80%, 6+ responses to be observed).

Results

We report efficacy results of the first 29 evaluable pts per cohort (Table 1). Grade 3+ toxicities (safety population) were 47% (1A n=36), 41% (2 n=32), 39% (3 n=33); most common anaemia (1A 36%, 2 19%,3 27%) & any other <10%. Discontinuation rates due to AEs were ≤10% in all cohorts. Preliminary translational results will be presented.

Table 1: Antitumour activity results

Conclusions

Celarasertib alone or in combination with olaparib has relevant clinical activity in rare gynae cancers. Demonstrable activity for combination in the non-clear cell ‘basket’ cohort, including carcinosarcoma, provides hypothesis-generating evidence for further investigation.

Clinical trial identification

ClinicalTrials.gov NCT04065269

Release date August 22 2019

Background

In randomized phase 3 NORA trial (NCT03705156), niraparib maintenance therapy with an individualized starting dose (ISD) significantly improved PFS (PFS; primary endpoint) and provided a favorable OS (OS; secondary endpoint) trend versus placebo, in patients with platinum-sensitive recurrent ovarian cancer (PSROC). Evaluating OS in randomized controlled trials can often be confounded by bias introduced by subsequent therapy. Considerable numbers of patients in placebo arm received subsequent PARPi therapy. This updated analysis aims to describe the treatment effect of niraparib versus placebo on OS adjusted for subsequent PAPPi use in placebo arm.

Methods

265 Chinese patients with PSROC who achieved a CR or PR to last platinum-based chemotherapy were randomized (2:1) to receive niraparib (n = 177) or placebo (n = 88). A majority of patients (249/265) received niraparib or placebo with an ISD based on baseline body weight and platelet count (200 mg for patients with baseline body weight < 77 kg or platelet count < 150,000/μL; otherwise, 300 mg). Kaplan-Meier method was used to describe OS. Hazard ratio was estimated using a Cox proportional model. Inverse probability of censoring weighting (IPCW) method was used to estimate the effect of niraparib versus placebo adjusted for subsequent PARPi use in placebo arm.

Results

As of the data cut-off of Sep. 23, 2022, an ad hoc interim OS analysis was conducted at 44% (117/265) maturity. Detailed data are provided in Table 1. 43% (38/88) patients [54% (19/35) in gBRCAmut and 36% (19/53) in non-gBRCAmut] in the placebo group received subsequent PARPi therapy.

Conclusions

Consistent with the OS results from the ITT analysis, the IPCW analysis further demonstrates favorable OS trend and supports positive benefit-risk profile of niraparib with ISD as maintenance therapy for PSROC.