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+. No OS benefit was seen in HRD− pts in any clinical risk subgroup. 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.Table: 32O

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.

Legal entity responsible for the study

ARCAGY Research, AstraZeneca, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and F. Hoffmann-La Roche.

Funding

ARCAGY Research, AstraZeneca, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and F. Hoffmann-La Roche.

Disclosure

D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: PharmaMar, Amgen, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards: Merck Serono; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Seagen, Immunogen, Genmab, Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for founding accdemic trial: MSD, Clovis Oncology, PharmaMar; Financial Interests, Institutional, Funding, Grant for founding acamemic trial: GSK; Financial Interests, Institutional, Invited Speaker, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, ENGOT trial with insitutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clnical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Personal, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Personal, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab; Non-Financial Interests, Personal, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation received: ImmunoGen, Clovis Oncology, Roche, Incyte; Non-Financial Interests, Personal, Principal Investigator, PI of several trials, no personal compensation received: Novartis; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial, no personal compensation received: Seagen; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trials, no personal compensation received: PharmaMar; Non-Financial Interests, Personal, Member, Board of Directors: GCIG; Other, Personal, Other, Grants for traveling: Roche, PharmaMar, AstraZeneca, Clovis Oncology, GSK. M. Mouret-Reynier: Financial Interests, Personal and Institutional, Advisory Board: Pfizer, Lilly, Novartis, MSD, AstraZeneca; Financial Interests, Personal and Institutional, Other, Clinical trial participation: Pfizer, Lilly, Novartis, MSD, AstraZeneca. P. Harter: Financial Interests, Personal, Advisory Board, Value includes honoraria for lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, includes honoraria for lectures: GSK, Roche, MSD; Financial Interests, Personal, Invited Speaker: Amgen, Stryker, Zailab, Eisai; Financial Interests, Personal, Advisory Board: Clovis, Immunogen, Novartis, Mersana; Financial Interests, Personal, Other, IDMC member: Sotio; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, GSK, Genmab, Immunogen; Financial Interests, Institutional, Funding: Seagen, Clovis; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca. E. Petru: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo. I.B. Vergote: Financial Interests, Personal, Advisory Board, Consulting: Agenus (2021), Aksebio China (2021), AstraZeneca (2021-2022), Bristol Myers Squibb (2021), Deciphera Pharmaceuticals (2021), Eisai (2021), F. Hoffmann-La Roche Ltd (2021), Genmab (2021), GSK (2021), Immunogen Inc. (2021-2022), Jazzpharma (2021-2022), Karyopharm (2021), MSD (2021-2022), Novocure (2020-2022), Novartis (2021), Oncoinvent AS (2021-2022), Seagen (2021), Sotio a.s. (2021-2022); Financial Interests, Institutional, Advisory Board, Consulting: AstraZeneca (2019-2020), Deciphera Pharmaceuticals (2020), Elevar Therapeutics (2020), F. Hoffmann-La Roche Ltd (2019-2020), Genmab (2019-2020), GSK (2019-2020), Mersana (2020), MSD (2019-2020), Oncoinvent AS (2019-2020), Sotio a.s. (2019-2020), Verastem Oncology (2020), Zentalis (2020), Amgen (Europe) 2019, Clovis Oncology Inc (2019), Carrick Therapeutics (2019), Millennium Pharmaceuticals (2019); Financial Interests, Institutional, Research Grant, Contracted Research (via KU Leuven): Oncoinvent AS (2019-2020); Financial Interests, Institutional, Research Grant, Contracted Research (via KU Leuven): Genmab (2019); Financial Interests, Institutional, Research Grant, Corporate sponsored research: Amgen (2019-2020), Roche (2019-2020). C. Lebreton: Financial Interests, Personal, Invited Speaker, Honoraria for presentation in educational events: Eisai, Clovis Oncology, MSD, GSK. P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi-Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Hecal, Lilly, Pierre Fabre, Seagen, Agendia; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi-Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BionTech, Cepheid; Non-Financial Interests, Personal, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v. C. Pisano: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, GSK; Financial Interests, Personal, Invited Speaker, Honoraria for presentation in educational events: Clovis. A. Hardy-Bessard: Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, GSK, Pfizer, Novartis. E. Pujade-Lauraine: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca; Financial Interests, Personal, Member, IDMC board: Agenus, Incyte; Financial Interests, Personal, Full or part-time Employment: ARCAGY Research. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmune, Eisai, SUTRO, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Personal, Principal Investigator: PAOLA1; Non-Financial Interests, Personal, Other, President: GINECO. All other authors have declared no conflicts of interest.

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%). 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. Table: 33O

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).

Legal entity responsible for the study

GSK (Waltham, MA, USA).

Funding

GSK (Waltham, MA, USA).

Disclosure

A.J. Gonzalez Martin: Financial Interests, Personal, Funding, manuscript funding: GSK; Financial Interests, Institutional, Research Grant: GSK, Roche; Financial Interests, Personal, Other, Consulting fees: Alkermes, Amgen, Genmab, ImmunoGen, MacroGenics, Merck Sharp & Dohme, Novartis, Oncoinvent, Pfizer/Merck, Sotio, Sutro; Financial Interests, Personal, Other, Consulting fees, honoraria fees, support for attending meetings: AstraZeneca, GSK, PharmaMar, Roche; Financial Interests, Personal, Other, Consulting fees, honoraria fees: Clovis Oncology. B. Pothuri: Financial Interests, Institutional, Research Grant: AstraZeneca, Celsion, Clovis Oncology, Eisai, Genentech/Roche, GSK, I-mab, Incyte, Karyopharm, Merck, Mersana, Sutro, Toray; Financial Interests, Personal, Other, Consulting fees: AstraZeneca, GSK, Merck, SeaGen; Financial Interests, Personal, Other, support for attending meetings: GOG Partners; Financial Interests, Personal, Advisory Board: Arquer Diagnostics, Atossa, Deciphera, Eisai, Elevar Therapeutics, GOG Foundation, I-mab, Lilly, Merck, Mersana, Sutro Biopharma, Tesaro/GSK, Toray, VBL Therapeutics. I.B. Vergote: Financial Interests, Institutional, Sponsor/Funding, corporate sponsorship research: Amgen, Roche; Financial Interests, Institutional, Research Grant, contracted research: Genmab, Oncoinvent AS; Financial Interests, Institutional, Other, consulting fee payments: Amgen (Europe) GmbH, AstraZeneca, Carrick Therapeutics, Clovis Oncology Inc, Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Oncoinvent AS, Octimet Oncology, Sotio, Verastem Oncology, Zentalis; Financial Interests, Personal, Other, consulting fees: Deciphera Pharmaceuticals, Jazz Pharmaceuticals, Oncoinvent AS; Financial Interests, Personal, Other, honoraria payments: Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, Jazz Pharmaceuticals, Karyopharm, MSD, Novartis, Novocure, Oncoinvent AS, Seagen, Sotio; Financial Interests, Institutional, Other, institutional travel support: Amgen, AstraZeneca, MSD, Roche, Tesaro; Financial Interests, Personal, Advisory Board: Agenus, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals (2021), Eisai, F. Hoffmann–La Roche Ltd, Genmab, GSK, Immunogen Inc, MSD, Novartis, Novocure, Seagen (2021), Sotio. W. Graybill: Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Speaker’s Bureau: GSK. M.R. Mirza: Financial Interests, Personal, Advisory Board: AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, Zai Lab; Financial Interests, Personal, Other, Consulting: AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, Zai Lab; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, GSK; Financial Interests, Institutional, Funding: Apexigen, AstraZeneca, Deciphera, GSK, Ultimovacs; Financial Interests, Personal, Member of the Board of Directors: Karyopharm; Financial Interests, Personal, Stocks/Shares: Karyopharm. C. McCormick: Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Immunogen, Clovis, Merck. D. Lorusso: Financial Interests, Personal, Other, consulting fees, honoraria: Amgen, MSD; Financial Interests, Personal, Other, consulting fees, honoraria, support for attending meetings and/or travel: AstraZeneca, Clovis Oncology, GSK, PharmaMar; Financial Interests, Personal, Other, consulting fees: Genmab, Immunogen, Seagen; Financial Interests, Personal, Other, support for attending meetings and/or travel: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, Merck Serono, MSD, Oncoinvest, PharmaMar, Seagen, Sutro; Non-Financial Interests, Personal, Member of the Board of Directors: GCIG; Financial Interests, Personal, Other, medical writing support: Clovis Oncology, GSK, MSD, PharmaMar; Financial Interests, Institutional, Funding, institutional funding for work in clinical trials: AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, PharmaMar, Roche, Seagen. G. Freyer: Financial Interests, Personal, Other, honoraria and consulting fees: GSK. F. Backes: Financial Interests, Personal, Other, personal fees: Agenus, AstraZeneca, CEC Oncolgoy, Clovis, Eisai, GSK, Immunogen, Merck, Myriad; Financial Interests, Personal, Research Grant: BeiGene, Clovis, Eisai, Immunogen, Merck, Natera. F. Heitz: Financial Interests, Personal, Other, honoraria: AstraZeneca, GSK, NovoCure, PhramaMar, Roche; Financial Interests, Personal, Advisory Board: NovoCure; Financial Interests, Personal, Leadership Role: AGO study group. A. Redondo Sanchez: Financial Interests, Institutional, Research Grant: Eisai, PharmaMar, Roche; Financial Interests, Personal, Other, honoraria: AstraZeneca, Clovis, Eisai, GSK, MSD, PharmaMar; Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis, Eisai, GSK, MSD, PharmaMar; Financial Interests, Personal, Invited Speaker, travel support: AstraZeneca, GSK, PharmaMar. R. Moore: Financial Interests, Personal, Other, personal fees: Abcodia Inc, Fujirebio Diagnostics Inc, Humphries Pharmaceutical; Financial Interests, Institutional, Research Grant: Angle Plc. C. Vulsteke: Financial Interests, Personal, Other, medical writing support: GSK; Financial Interests, Personal, Invited Speaker, consulting fees: Atheneum Partners, Bristol Myers Squib, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme, Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme; Financial Interests, Personal, Other, travel support: Pfizer, Roche. R.E. O'Cearbhaill: Financial Interests, Personal, Advisory Board: Bayer, Carina Biotech, Fresenius Kabi, Tesaro/GSK, Regeneron, Seattle Genetics, R-Pharm, Immunogen; Financial Interests, Personal, Other, personal fees: GOG Foundation; Financial Interests, Personal, Other, travel fees: Hitech Health; Non-Financial Interests, Institutional, Research Grant: AstraZeneca/Merck; Financial Interests, Institutional, Research Grant: Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Regeneron, Sellas Life Sciences, StemcentRx, Syndax, TapImmune Inc, TCR2 Therapeutics. I. Malinowska: Financial Interests, Personal, Full or part-time Employment: GSK. L. Shtessel: Financial Interests, Personal, Full or part-time Employment: GSK. W. York: Financial Interests, Personal, Full or part-time Employment: GSK. B.J. Monk: Financial Interests, Personal, Other, consulting fees: Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Macrogenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, VBL; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, Tesaro/GSK.

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. 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: 34O

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

NCT04065269.

Legal entity responsible for the study

The Institute of Cancer Research.

Funding

AstraZeneca UK Limited.

Disclosure

S. Banerjee: Financial Interests, Personal, Advisory Board: Amgen, Immunogen, Mersana, Merck Sereno, MSD, Roche, AstraZeneca, GSK, Oncxerna, Shattuck Labs, Novartis, Epsilogen, Seagen, Eisai; Financial Interests, Personal, Invited Speaker: Clovis, Pfizer, AstraZeneca, GSK, Takeda, Amgen, Medscape, Research to Practice, Peerview; Financial Interests, Personal, Stocks/Shares: PerciHealth; Financial Interests, Institutional, Research Grant: AstraZeneca, GSK; Non-Financial Interests, Personal, Principal Investigator, Phase II clinical trial Global lead, ENGOTov60/GOG3052/RAMP201: Verastem; Non-Financial Interests, Personal, Principal Investigator, ENGOT-GYN1/ATARI phase II international trial (academic sponsored): AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, Academic sponsored trial PI (MONITOR-UK): GSK; Non-Financial Interests, Personal, Other, Member of membership committee: ESGO; Non-Financial Interests, Personal, Advisory Role, Medical advisor to UK ovarian cancer charity: Ovacome Charity. A. Leary: Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Invited Speaker, Educational: GSK, Medscape, Onko+; Financial Interests, Institutional, Other, Steering committee: MSD; Financial Interests, Institutional, Advisory Board: GSK, AstraZeneca, Clovis, Ability Pharma, MSD, Tesaro, Merck Serono, Apmonia, Blueprint; Financial Interests, Institutional, Invited Speaker, Educational: Kephren publishing; Financial Interests, Institutional, Other, Consultancy: Orion; Financial Interests, Institutional, Invited Speaker: Tesaro, AstraZeneca, Clovis; Financial Interests, Personal, Other, Consultancy: GLG; Financial Interests, Institutional, Research Grant, PI translational research: ARCAGY-GINECO, Sanofi, AstraZeneca; Financial Interests, Institutional, Funding, CI clinical trial: AstraZeneca; Financial Interests, Institutional, Research Grant, Int CI clinical trial: OSE immuno; Financial Interests, Institutional, Funding, PI clinical trial: Agenus, BMS, Iovance, GSK; Financial Interests, Institutional, Funding, PI 5 clinical trials: Roche; Financial Interests, Institutional, Funding, PI 2 clinical trials: AstraZeneca; Financial Interests, Institutional, Funding, PI 3 clinical trials and steering committee: MSD; Non-Financial Interests, Institutional, Other, Academic research project: Owkin, LXRepair; Non-Financial Interests, Personal, Proprietary Information, IDMC member: Clovis; Non-Financial Interests, Personal, Proprietary Information, IDMC chair: Pfizer. S. Lheureux: Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Eisai, Merck, Novartis; Financial Interests, Personal, Invited Speaker: GSK, Roche; Financial Interests, Institutional, Research Grant, Academic trial: GSK; Financial Interests, Institutional, Invited Speaker: Repare Therapeutics, Merck, AstraZeneca, Regeneron, GSK, Roche, Seagen; Financial Interests, Institutional, Research Grant: Roche. A.R. Clamp: Financial Interests, Personal, Invited Speaker: Clovis Oncology, AstraZeneca; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Merck, Verastem, Novartis, Advenchen Laboratories, AstraZeneca; Non-Financial Interests, Personal, Advisory Role: National Institute of Health and Care Excellence. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmune, Eisai, SUTRO, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Personal, Principal Investigator: PAOLA1; Non-Financial Interests, Personal, Other, President: GINECO. C. Gourley: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board, Both personal and institutional: AstraZeneca, MSD, GlaxoSmithKline; Financial Interests, Personal, Invited Speaker, Both personal and institutional: AstraZeneca, MSD, GSK, Clovis, Chugai, Takeda; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Aprea, Nucana, Medannexin; Financial Interests, Institutional, Invited Speaker: GlaxoSmithKline, BerGenBio. R.M. Glasspool: Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Clovis Oncology, MSD, Immunogen, Sotio; Financial Interests, Institutional, Other, Institutional Consultancy fees: Novartis; Financial Interests, Institutional, Research Grant: Clovis Ongocology, Lilly/Ignyta, Boehringer Ingelheim; Financial Interests, Personal, Other, Conference fees for medical conferences: GSK; Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca, GSK, Novartis, Oncology Venture, Clovis Oncology. R. Natrajan: Financial Interests, Institutional, Research Grant: Pfizer. C. Lord: Financial Interests, Institutional, Research Grant: AstraZeneca, Merck KGaA; Financial Interests, Personal, Advisory Board: Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics, Pontifax, Astex, Neophore, GSK; Financial Interests, Personal, Stocks/Shares: Tango, Ovibio, Hysplex, Tesselate; Financial Interests, Personal and Institutional, Proprietary Information, Rewards to Inventors scheme: Institute of Cancer Research. All other authors have declared no conflicts of interest.

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 the table. 43% (38/88) patients [54% (19/35) in gBRCAmut and 36% (19/53) in non-gBRCAmut] in the placebo group received subsequent PARPi therapy. Table: 35O

OS summary for ITT population and by gBRCA status

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.

Legal entity responsible for the study

Zai Lab.

Funding

This work was supported by Zai Lab (No grant number). The work was also partially supported by the National Major Scientific and Technological Special Project for ‘Significant New Drugs Development’ in 2018, China [grant number 2018ZX09736019].

Disclosure

X. Zhen: Financial Interests, Personal, Full or part-time Employment: Zai Lab (US) LLC; Financial Interests, Personal, Stocks/Shares: Zai Lab (US) LLC. J. Dong: Financial Interests, Personal, Full or part-time Employment: Zai Lab (Shanghai) Co., Ltd; Financial Interests, Personal, Stocks/Shares: Zai Lab (Shanghai) Co., Ltd. C. Zhang: Financial Interests, Personal, Full or part-time Employment: Zai Lab (Shanghai) Co., Ltd; Financial Interests, Personal, Stocks/Shares: Zai Lab (Shanghai) Co., Ltd. J. Hou: Financial Interests, Personal, Full or part-time Employment: Zai Lab (Shanghai) Co., Ltd; Financial Interests, Personal, Stocks/Shares: Zai Lab (Shanghai) Co., Ltd. M.R. Mirza: Financial Interests, Personal, Advisory Board: AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, Zai Lab; Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK, Karyopharm; Financial Interests, Personal, Stocks/Shares: Karyopharm; Financial Interests, Institutional, Research Grant: GSK, AstraZeneca, Ultimovacs, Apexigen; Financial Interests, Institutional, Invited Speaker: Deciphera; Non-Financial Interests, Personal, Advisory Role: Ultimovacs, Apexigen. All other authors have declared no conflicts of interest.