Efficacy of Niraparib by Timing of Surgery and Residual Disease: a Post Hoc Analysis of Patients

in the PRIMA/ENGOT-OV26/GOG-3012 StudyRoisin O’Cearbhaill,1 Jose-Alejandro Pérez-Fidalgo,2 Bradley J. Monk,3 Ignacio Tusquets,4 Colleen McCormick,5 Jose Fuentes-Pradera,6 Richard G. Moore,7 Christof Vulsteke,8 Mark S. Shahin,9 Frederic Forget,10 William H. Bradley,11 Sakari Hietanen,12

David O'Malley,13 Anne Dørum,14 Brian M. Slomovitz,15 Klaus Baumann,16 Frédéric Selle,17 Paula M. Calvert,18 Grazia Artioli,19 Tally Levy,20 Aalok Kumar,21 Izabela A. Malinowska,22 Yong Li,22 Divya Gupta,22 Antonio González-Martin23

1GOG and the Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA; 2Department of Medical Oncology, INCLIVA University Hospital of Valencia, CIBERONC, Valencia, Spain; 3Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine, Phoenix, AZ, USA; 4Medical Oncology Department, Hospital del Mar, Barcelona, Spain; 5GOG and Legacy Medical Group Gynecologic Oncology, Portland, OR, USA; 6Servicio de Oncologia, Hospital de Valme, Sevilla, Spain; 7Division of Gynecologic Oncology, Wilmot Cancer Institute, Department of Obstetrics and Gynecology, University of Rochester, Rochester, NY, USA;

8BGOG and the Department of Medical Oncology and Hematology, AZ Maria Middelares, Ghent, Belgium, and the Department of Molecular Imaging, Pathology, Radiotherapy, and Oncology, Center for Oncological Research, Antwerp University, Antwerp, Belgium; 9Abington Hospital-Jefferson Health, Sidney Kimmel Cancer Center of Thomas Jefferson University, Willow Grove, PA, USA; 10Department of Medical Oncology, Libramont Hospital, Libramont, Belgium; 11GOG and the Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA; 12Department of Obstetrics and Gynecology, Turku University Hospital, Turku, Finland; 13James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA;

14Gynecologic Oncology, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway; 15Broward Health, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA; 16Arbeitsgemeinschaft Gynäkologische Onkologie and the Department of Gynecology and Obstetrics, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany; 17GINECO and Groupe Hospitalier Diaconesses-Croix Saint Simon, Paris, France; 18Cancer Trials Ireland, Dublin, Ireland; 19ULSS 3 Serenissima, U.O.C. Oncologia ed Ematologia Oncologica, Mirano, Venice, Italy; 20Department of Obstetrics and Gynecology, Wolfson Medical Center, Sackler School of Medicine, Tel Aviv University, Holon, Israel;

21Department of Medical Oncology, BC Cancer, Fraser Valley Cancer Centre, Surrey, BC, Canada; 22GlaxoSmithKline, Waltham, MA, USA; 23Grupo Español de Investigación en Cáncer de Ovario (GEICO) and Medical Oncology Department, Clínica Universidad de Navarra, Madrid, Spain

Background

Conclusions

● Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved as maintenance treatment for patients with newly diagnosed advanced or recurrent ovarian cancer following a response to platinum-based chemotherapy (CT) doublet1

● This study showed that niraparib following first-line treatment improved progression-free survival (PFS) in the overall intention-to-treat (ITT) population (hazard ratio [HR], 0.62; 95% CI, 0.50–0.76) and in the homologous repair-deficient (HRd) population (HR, 0.43; 95% CI, 0.31–0.59)2

● In this post hoc analysis, the impact of residual disease after PDS or IDS on the efficacy of niraparib was similar across subgroups

● Patients with IDS and VRD had the highest reduction in the risk of progression, demonstrating the efficacy of niraparib maintenance in the hardest to treat patients with newly diagnosed ovarian cancer

● The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study was a double-blind, placebo (pbo)-controlled, phase 3 trial that evaluated niraparib in patients with newly diagnosed, advanced, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer with a complete response (CR) or partial response (PR) to first-line CT (Figure 1)̶ Patients were considered at a high risk for disease progression on the basis of

their clinical characteristics● This post hoc analysis presents the efficacy of niraparib, measured by PFS, based on

time of surgery and residual disease status̶ Patients either underwent PDS or received NACT/IDS̶ Residual disease was defined as no visible residual disease (R0, NVRD) or

residual visible disease (R1/R2, VRD) on the basis of physician’s assessment at the completion of primary surgery

● This analysis was not powered to determine differences among the subgroups

Methods

● Data cutoff was May 2019● In total, 733 patients were randomized in the PRIMA study● Patient demographics and baseline characteristics are shown in Table 1

Results

Results (cont’d)Figure 3. PFS by Surgical Status and VRD Status Efficacy

● Efficacy outcomes by surgical timing, either PDS or IDS, and postoperative residual disease status, either NVRD or VRD, are shown in Table 2

● Patients who underwent PDS or IDS had similar efficacy with niraparib maintenance treatment versus pbo in the ITT population (Figure 2)

● Niraparib treatment reduced risk of progression by 42% in patients who received PDS and had VRD, by 35% in those with IDS and NVRD, and by 59% in those with IDS and VRD (Figure 3)

● Efficacy was not evaluable for patients with PDS and NVRD because of low sample size

Figure 2. PFS by Surgical Status

Conflicts of InterestDr. O'Cearbhaill reports personal fees from GlaxoSmithKline; institutional research support from NIH/NCI Cancer Center Support Grant (P30 CA008748); and service as a noncompensated steering committee member for the PRIMA (Niraparib) study and DUO-O (Olaparib) study. Dr. Perez-Fidalgo reports personal fees from GlaxoSmithKline, AstraZeneca, Clovis, Abilify Pharma, Clinigen, Roche, and Amgen; and institutional grants from GlaxoSmithKline. Dr. Monk reports consulting fees from Abbvie, Amgen, Aravive, AstraZeneca, Clovis, GOG Foundation, Gradalis, ImmunoGen, Laekna Health Care, Merck, Mersana, Myriad, Nucana, Oncomed, Oncoquest, Pfizer, Roche/Genentech, and GlaxoSmithKline; speakers’ bureau fees from AstraZeneca, Clovis, Merck, Roche/Genentech, and GlaxoSmithKline; and honoraria from Abbvie, Amgen, Aravive, AstraZeneca, Clovis, GOG Foundation, Gradalis, ImmunoGen, Laekna Health Care, Merck, Mersana, Myriad, Nucana, Oncomed, Oncoquest, Pfizer, Roche/Genentech, and GlaxoSmithKline. Dr. Tusquets reports personal fees from Roche Pharma AG and Celgene; institutional grants from Roche; and travel support from Roche. Dr. Fuentes-Pradera has nothing to disclose. Dr. Moore reports personal fees from Fujirebio Diagnostics Inc., Abcodia Inc., and Humphries Pharmaceutical; and institutional grants from Angle Plc. Dr. Vulstek has nothing to disclose. Dr. Shahin reports personal fees from GlaxoSmithKline, Merck, AstraZeneca, Clovis Oncology, and Pacira Pharmaceuticals Inc.; and institutional grants from GlaxoSmithKline. Dr. O’Malley reports personal fees from Immunogen, Eisai, Agenus, and GlaxoSmithKline; consultant/advisory board for Clovis, Ambry, Abbvie, Janssen/J&J, Regeneron, Novacure, Myriad Genetics, Tarveda, Amgen, VentiRx, Array Biopharma, EMD Serono, and Ergomed; steering committee for Genentech/Roche and Merck; institutional funding from Ajinomoto Inc., Ludwig Cancer Research, Stemcentrx Inc., Cerulean Pharma, GOG Foundation, BMS, Serono Inc., Tracon Pharmaceuticals, Yale University, New Mexico Cancer Care Alliance, INC Research Inc., inVentiv Health Clinical, Iovance Biotherapeutics Inc., and PRA International. Dr. Slomovitz reports consulting/advisory fees from GlaxoSmithKline. Dr. Selle reports personal fees from Roche, AstraZeneca, GlaxoSmithKline, Clovis, MSD, and PharmaMar; and travel support from Roche, AstraZeneca, GlaxoSmithKline, MSD, and PharmaMar. Dr. Kumar reports personal fees from GlaxoSmithKline and AstraZeneca. Dr. González-Martín reports personal fees and nonfinancial support from AstraZeneca; grant and personal fees from GSK, Clovis Oncology, Roche Holding AG, Merck & Co., Inc., Genmab, Inmunogen, Pharma Mar, S.A., and Oncoinvent AS. Drs. McCormick, Vulstek, Forget, Bradley, Hietanen, Dørum, Baumann, Calvert, Artioli, and Levy have nothing to disclose. Drs. Malinowska, Li, and Gupta are employees of GlaxoSmithKline.

● This ad hoc analysis evaluated the efficacy of niraparib maintenance in patients by surgical status—primary debulking surgery (PDS) or neoadjuvant chemotherapy/ interval debulking surgery (NACT/IDS)—and residual disease status in the ITT population

Objectives

Acknowledgments• We thank the patients and their families for their participation in this study, as well as the study

teams at each of the study sites. • Writing and editorial support, funded by GlaxoSmithKline (Waltham, MA, USA) and coordinated

by GlaxoSmithKline, were provided by Eric Scocchera, PhD, and Celia Nelson, BA, of AshfieldHealthcare Communications (Middletown, CT, USA). This study (NCT02655016) was funded by GlaxoSmithKline.

References1. ZEJULA® (niraparib) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; April 2020.2. González-Martín A, et al. N Engl J Med 2019;381:2391–2402.

Table 1. Patient Demographics and Baseline CharacteristicsFIGO Stage III FIGO Stage IV Overall

CharacteristicNiraparib

n=318Placebo n=158

Niraparibn=169

Placebon=88

NiraparibN=487

PlaceboN=246

Stage at initial diagnosis, n (%) III 318 (100) 158 (100) 0 0 318 (65.3) 158 (64.2)

IV 0 0 169 (100) 88 (100) 169 (34.7) 88 (35.8)

Best response to 1L platinum-based CT, n (%)CR 219 (68.9) 110 (69.6) 118 (69.8) 62 (70.5) 337 (69.2) 172 (69.9)

PR 99 (31.1) 48 (30.4) 51 (30.2) 26 (29.5) 150 (30.8) 74 (34.1)

Debulking surgery, n (%)PDS 114 (35.8) 56 (35.4) 44 (26.0) 22 (25.0) 158 (32.4) 78 (31.7)

IDS 200 (62.9) 99 (62.7) 116 (68.6) 66 (75.0) 316 (64.9) 165 (67.1)

No surgery 4 (1.3) 3 (1.9) 9 (5.3) 0 13 (2.7) 3 (1.2)

Residual disease status after PDS, n (%)NVRD 1 (0.3) 0 21 (12.4) 15 (17.0) 22 (4.5) 15 (6.1)

VRD 104 (32.7) 52 (32.9) 20 (11.8) 7 (8.0) 124 (25.5) 59 (24.0)

Missinga 9 (2.8) 4 (2.5) 3 (1.8) 0 12 (2.5) 4 (1.6)

Residual disease status after IDS, n (%)NVRD 128 (40.3) 62 (39.2) 74 (43.8) 40 (45.5) 202 (41.5) 102 (41.5)

VRD 58 (18.2) 30 (19.0) 38 (22.5) 23 (26.1) 96 (19.7) 53 (21.5)

Missinga 14 (4.4) 7 (4.4) 4 (2.4) 3 (3.4) 18 (3.7) 10 (4.1)

aResidual disease burden information was not collected for the patients enrolled in original protocol.

1L, first-line; BICR, blinded independent central review; HRnd, homologous recombination status not determined; HRp, homologous recombination proficient; OC, ovarian cancer; OS, overall survival; PFS2, progression-free survival 2; PRO, patient-reported outcome; QD, once daily; TFST, time to first subsequent therapy.

Figure 1. Trial Design

Niraparib Placebo

Endpoint assessment

Primary endpoint: PFS by BICRKey secondary endpoint: OSSecondary endpoints: PFS2, TFST, PROs, safety

2:1 randomization

Patients with newly diagnosed OC at high risk for recurrence after response to 1L platinum-based

chemotherapy• NACT administered: yes or no • Best response to 1L platinum therapy: CR or PR• Tissue homologous recombination test status: HRd or HRp/HRnd

– Determined by Myriad myChoice® CDx next-generation sequencing test

Stratification factors

• Primary endpoint tested hierarchically: first in patients with HRdtumors, then in the ITT/overall population

• Efficacy by timing of surgery and residual disease were post hoc analyses

Analyses

One-third of patients enrolled received the following individualized starting dose:• Body weight ≥77 kg and platelet count ≥150,000/μL: 300 mg QD• Body weight <77 kg and/or platelet count <150,000/μL: 200 mg QD

Protocol amendment, November 2017

In patients who received PDS, 16 patients’ residual disease status was unknown. In patients who received IDS, 28 patients’ residual disease status was unknown.

Table 2. Efficacy Results by Time of Surgery and VRD Status ITT NVRD (R0)a VRD (R1/R2)a

All patientsNHR (95% CI)PmPFS (nir vs pbo)ΔmPFS

733b0.62 (0.5–0.76) <0.000113.8 vs 8.2 months5.6 months

PDSNHR (95% CI)mPFS (nir vs pbo)ΔmPFS

236c0.67 (0.468–0.964)13.7 vs 8.2 months5.5 months

37NEd

NEd

NEd

1830.58 (0.391–0.864)11.8 vs 7.8 months4 months

IDS/NACTNHR (95% CI)mPFS (nir vs pbo)ΔmPFS

481e0.57 (0.441–0.731)14.2 vs 8.2 months6 months

3040.65 (0.461–0.91)18.2 vs 10.9 months7.3 months

1490.41 (0.269–0.620)11.1 vs 5.6 months5.5 months

aResidual disease was defined as no visible residual disease (R0, NVRD) or residual visible disease (R1/R2, VRD) on the basis of physician’s assessment at the completion of primary surgery; b16 patients had no debulking surgery;c16 patients had unknown residual disease status; dAnalysis is not relevant because of the small number of patients; e28 patients had unknown residual disease status; mPFS, median progression-free survival; NE, not evaluable; nir, niraparib.

Presented at the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting

on Women’s Cancer, Virtual Meeting, March 19–25, 2021.

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