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OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab

Open AccessPublished:June 08, 2022DOI:https://doi.org/10.1016/j.ygyno.2022.05.020

      Highlights

      • OVARIO enrolled patients with primary advanced-stage ovarian cancer, including high-risk cases.
      • In the overall population, 62% of patients were progression-free at the 18-month primary endpoint.
      • After a median follow-up of 28.7 months, median PFS was 19.6 months (overall), 28.3 months (HRd), and 14.2 months (HRp).
      • The most common any-grade adverse events related to niraparib and/or bevacizumab were thrombocytopenia, fatigue, and anemia.

      Abstract

      Objective

      To assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer.

      Methods

      This multicenter, phase II, single-arm, open-label study enrolled adult patients with stage IIIB to IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have an attempt at debulking surgery and have a complete response, partial response, or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab. The primary endpoint was the progression-free survival (PFS) rate at 18 months. Secondary endpoints included PFS, overall survival, and safety.

      Results

      Among the 105 evaluable patients, the PFS rate at 18 months was 62% (95% CI 52–71%) in the overall population and 76% (95% CI 61–87) in the homologous recombination deficient (HRd), 47% (95% CI 31–64%) in the HR proficient (HRp), and 56% (95% CI 31–79%) in the HR not determined (HRnd) subgroups (December 24, 2020, cutoff). After a median follow-up time of 28.7 months (IQR, 23.9–32.5 months), median PFS was 19.6 months (95% CI 16.5–25.1) in the overall population (N = 105) and 28.3 months (95% CI 19.9–NE), 14.2 months (95% CI 8.6–16.8), and 12.1 months (95% CI 8.0–NE) in the HRd, HRp, and HRnd subgroups, respectively (June 16, 2021, cutoff). The most common any-grade treatment-related adverse events (related to niraparib and/or bevacizumab) were thrombocytopenia (74/105), fatigue (60/105), and anemia (55/105; December 24, 2020, cutoff).

      Conclusion

      Niraparib + bevacizumab first-line maintenance therapy displayed promising PFS results. Safety was consistent with the known safety profiles of niraparib and bevacizumab as monotherapy.

      Graphical abstract

      Keywords

      1. Introduction

      Worldwide, ovarian cancer accounts for approximately 5% of cancer-related deaths in women [
      • Sung H.
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      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ] and will result in an estimated 12,810 deaths in the United States in 2022 alone [
      • Sung H.
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      • Jemal A.
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      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ,
      • Siegel R.L.
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      Cancer statistics, 2022.
      ]. Most patients present with advanced disease at diagnosis, which is associated with a high rate of recurrence and poor overall survival [
      • Siegel R.L.
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      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2021.
      ]. In patients with stage III or IV ovarian cancer who have undergone primary debulking surgery, the addition of an antiangiogenic agent, bevacizumab, to first-line platinum-based chemotherapy followed by bevacizumab maintenance therapy results in an improved progression-free survival (PFS) compared with patients treated with chemotherapy alone [
      • Burger R.A.
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      • Bookman M.A.
      • Fleming G.F.
      • Monk B.J.
      • Huang H.
      • et al.
      Incorporation of bevacizumab in the primary treatment of ovarian cancer.
      ,
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      • Colombo N.
      • Sessa C.
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      Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ].
      In addition to maintenance treatment with bevacizumab, maintenance treatment with poly(ADP-ribose) polymerase (PARP) inhibitors has also been shown to improve PFS in patients with ovarian cancer in both the first-line and recurrent settings [
      • Gonzalez-Martin A.
      • Pothuri B.
      • Vergote I.
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      • Graybill W.
      • Mirza M.R.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ,
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      • Redondo A.
      • et al.
      Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.
      ,
      • Moore K.
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      • Oaknin A.
      • Friedlander M.
      • et al.
      Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • Pujade-Lauraine E.
      • Ledermann J.A.
      • Selle F.
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      • Penson R.T.
      • Oza A.M.
      • et al.
      Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial.
      ]. PARP inhibitors function by preventing the repair of single-strand DNA breaks and inducing double-strand DNA breaks that cannot be repaired in tumor cells with homologous recombination deficiency (HRD) [
      • Konecny G.E.
      • Kristeleit R.S.
      PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions.
      ]. Within the tumor microenvironment, inhibition of vascular endothelial growth factor (VEGF) can contribute to hypoxia, which can drive genomic instability through the alteration of DNA damage repair pathways, including homologous recombination [
      • Scanlon S.E.
      • Glazer P.M.
      Hypoxic stress facilitates acute activation and chronic downregulation of fanconi anemia proteins.
      ,
      • Bindra R.S.
      • Schaffer P.J.
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      • Woo J.
      • Maseide K.
      • Roth M.E.
      • et al.
      Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells.
      ]. Therefore, at the time of study design, it was hypothesized that antiangiogenic agents targeting VEGF may increase the sensitivity of tumors to PARP inhibitors. Trials evaluating this hypothesis included NSGO-AVANOVA2/ENGOT-ov24 and PAOLA-1 [
      • Mirza M.R.
      • Avall Lundqvist E.
      • Birrer M.J.
      • dePont Christensen R.
      • Nyvang G.B.
      • Malander S.
      • et al.
      Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial.
      ,
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Perol D.
      • Gonzalez-Martin A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ].
      Niraparib is an approved PARP inhibitor in the maintenance setting of first-line or recurrent ovarian cancer after response to platinum-based chemotherapy. To investigate the potential clinical benefit of combined maintenance treatment with a PARP inhibitor and an anti-VEGF agent, the single-arm, open-label phase II OVARIO trial (NCT03326193) was conducted to evaluate the efficacy and safety of niraparib plus bevacizumab maintenance therapy for patients with newly diagnosed advanced ovarian cancer with stage IIIB–IV disease following a complete or partial response to first-line platinum-based chemotherapy with bevacizumab.

      2. Methods

      2.1 Patients

      Female patients ≥18 years of age with newly diagnosed advanced (International Federation of Gynecology and Obstetrics [FIGO] stage IIIB to IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer were eligible to participate in the study. Patients with nonmucinous epithelial ovarian cancer and germline BRCA (gBRCA) mutation were eligible, and patients with high-grade serous or endometrioid histology were eligible regardless of HRD or gBRCA status. Patients must have undergone one attempt at optimal debulking surgery and completed 6–9 treatment cycles of first-line platinum-based chemotherapy with a complete response (CR), partial response (PR), or no evidence of disease (NED) based on investigator assessment. Intraperitoneal or neoadjuvant chemotherapy and interval debulking surgery were allowed, as were patients with or without residual disease after primary debulking surgery. Patients with inoperable disease were excluded. Eligible patients must have received a minimum of 3 cycles of bevacizumab in combination with the last 3 cycles of platinum-based chemotherapy; in patients who underwent interval debulking surgery, patients must have received 2 cycles of bevacizumab in combination with the last 3 cycles of platinum-based chemotherapy. In addition, patients were required to have cancer antigen-125 (CA-125) levels in the normal range or have had a more than 90% decrease in CA-125 levels during first-line therapy that was stable for at least 7 days. Tumor homologous recombination deficiency (HRD) testing (myChoice® HRD test, Myriad Genetics, Inc., Salt Lake City, UT) during the screening period was required, and this assay was also used to determine tumor BRCA status. Patient samples were centrally tested, and patients were classified as HR deficient (HRd, HRD score ≥ 42), HR proficient (HRp, HRD score <42), or HR status not determined (HRnd). Please see Appendix S1 for the full list of OVARIO eligibility criteria.

      2.2 Study design and treatment

      The OVARIO (NCT03326193) phase II, single-arm, open-label study was conducted in the United States across 28 study sites. A full list of study sites can be found in Appendix S2. Patients initiated maintenance therapy with niraparib and bevacizumab within 12 weeks of the last cycle of chemotherapy. Patients received an individualized starting dose (ISD) of niraparib. Patients with a baseline body weight of <77 kg or a platelet count of <150,000/μL received niraparib 200 mg orally once daily; however, patients with a baseline body weight of ≥77 kg and a platelet count of ≥150,000/μL were administered a starting dose of 300 mg orally once daily. A dose interruption (<28 days) or dose reduction was permitted based on adverse treatment effects. Dose modifications were not based on changes to the patient's actual body weight during study participation. Patients could continue niraparib maintenance therapy for up to 3 years or until disease progression, unacceptable toxicity, investigator's decision, or death. Bevacizumab 15 mg/kg was administered via intravenous (IV) infusion on day 1 of each 21-day dosing cycle for up to a maximum of 15 months.
      The study, designed and sponsored by GlaxoSmithKline (formerly Tesaro), was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practices, and local laws. The protocol was approved by independent ethics committees and the relevant institutional review board at each site, and all patients gave informed written consent.

      2.3 Endpoints and assessments

      The primary efficacy endpoint was a landmark PFS rate at 18 months, defined as the proportion of patients without disease progression or death within 18 months after initiation of niraparib plus bevacizumab combination maintenance therapy; disease progression was investigator-assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included PFS, time to first subsequent treatment (TFST), time to second subsequent treatment (TSST), and overall survival (OS). The PFS rate at 18 months and median PFS were also assessed for the following prespecified subgroups: age (<65 or ≥ 65 years), Eastern Cooperative Oncology Group performance status (0 or 1), FIGO stage at diagnosis (III or IV), HRD testing status (HRd, HRp, or HRnd), BRCA status (BRCA mutated [BRCAm], BRCA wild type [BRCAwt], or BRCA not determined [BRCAnd]), chemotherapy received during first-line platinum-based treatment (neoadjuvant or adjuvant), macroscopic postoperative visible residual disease status (yes, no, or unknown), and best response during first-line platinum-based treatment (NED/CR or PR). Exploratory endpoints included PFS rate at 6 and 12 months. Tumor assessments were performed every 12 weeks for the first 48 weeks, then every 24 weeks until disease progression. Safety outcomes included the incidence of treatment-related adverse events (TRAEs), serious adverse events, and treatment discontinuations and dose reductions due to adverse events. All adverse events were classified using Medical Dictionary for Regulatory Activities (MedDRA) version 22.0 or later; Common Terminology Criteria for Adverse Events (CTCAE) guidelines were used for grading adverse event severity. In response to the COVID-19 pandemic, study sites were provided with written guidance to accommodate COVID-19–related safety precautions, including the use of local laboratories and radiology centers, use of central and remote monitoring programs, and use of a telemedicine platform to facilitate remote monitoring of adverse events, concomitant medications, and protocol deviations. Patient-reported outcomes were assessed using the Functional Assessment of Cancer Therapy—Ovarian Symptom Index (FOSI); FOSI data were collected every 6 weeks for 6 months and then every 12 weeks thereafter.

      2.4 Statistical analysis

      A sample size of approximately 90 patients was determined sufficient to provide an 11% precision on the 95% exact CIs of the PFS rate at 18 months, assuming a true PFS rate at 18 months of 48%, which corresponds to a median PFS of 17 months based on exponential assumption. The primary endpoint was selected to test a 30% increase in benefit over bevacizumab alone based on data from the GOG-0218 trial. This trial reported a median PFS of 14.1 months in patients with primary advanced ovarian cancer who were treated with bevacizumab plus chemotherapy for first-line therapy [
      • Burger R.A.
      • Brady M.F.
      • Bookman M.A.
      • Fleming G.F.
      • Monk B.J.
      • Huang H.
      • et al.
      Incorporation of bevacizumab in the primary treatment of ovarian cancer.
      ]. PFS proportions were estimated by a frequency analysis of the number of intent-to-treat (ITT) patients without documented progression or death by months 6, 12, or 18, divided by the number of ITT patients. The 95% exact CIs were also provided. Summary statistics were reported for all variables: number and percentage for categorical variables, and number of patients, mean, standard deviation, median, minimum, and maximum for continuous variables. Time-to-event analyses were performed using Kaplan-Meier methodology. Median time-to-event and its two-sided 95% CIs from Brookmeyer and Crowley method with log-log transformation were reported when appropriate. No formal statistical testing was performed. The analysis of the primary endpoint was performed using data from the December 24, 2020, clinical cutoff date. Since the event rate (progression or death) was less than 50% at the time of the primary analysis of PFS, an additional data cut was taken on June 16, 2021, to conduct the secondary analyses of PFS, TFST, TSST, and OS.

      3. Results

      3.1 Patients

      Between December 12, 2017, and February 14, 2019, 119 patients were assessed for eligibility, and 105 patients were enrolled and received at least 1 study treatment (niraparib or bevacizumab; safety population). Because all enrolled patients received at least 1 dose of niraparib, the safety and efficacy populations were identical (n = 105; Fig. 1). Overall, 78.1% (82/105) of patients started at a niraparib dose of 200 mg. Among 82 patients that received a starting dose of 200 mg: 64 patients had low body weight alone, 2 had low platelets alone, and 12 had both low body weight and low platelet count. At the December 24, 2020, clinical cutoff date, 23.8% (25/105) of patients were still receiving niraparib. For bevacizumab, 41.0% (43/105) of patients completed the planned treatment course, and no patients were still receiving bevacizumab.
      Fig. 1
      Fig. 1Trial profile and patient disposition as of the December 24, 2020, clinical cutoff date.
      aTest inconclusive or failed or insufficient tissue.
      bDiscontinuation due to a treatment emergent-adverse event, regardless of whether the investigator determined the event to be related to study treatment.
      cOne patient never received any bevacizumab before discontinuing niraparib treatment.
      dPer protocol, bevacizumab use was limited to a total of 15 months, inclusive of approximately 5 months of bevacizumab with chemotherapy and approximately 10 months of bevacizumab as maintenance therapy.
      Abbreviations: HRd, homologous recombination deficient; HRnd, homologous recombination not determined; HRp, homologous recombination proficient.
      At baseline, median patient age was 60 years, and approximately half of patients had a history of hypertension (52/105, 49.5%; Table 1). Most patients had FIGO stage III disease at diagnosis (82/105, 78.1%), and 62.9% (66/105) of patients received neoadjuvant chemotherapy with interval debulking surgery before enrollment. Macroscopic postoperative residual disease was reported in 26.7% (28/105) of patients. At baseline, patients had received a median (range) of 6 (4–10) cycles of platinum-based chemotherapy and 3 (2−11) cycles of bevacizumab treatment. Just over half of the patients (61/105, 58.1%) had NED or experienced a CR after debulking surgery and first-line platinum-based chemotherapy. A total of 27.6% (29/105) of patients had a deleterious tumor BRCA mutation. Nearly half (46.7%) of patients had tumors that were HRd (49/105), and 36.2% (38/105) had tumors that were HRp. The remaining 17.1% (18/105) of patients had tumors that were classified as HRnd owing to inconclusive results (14/105) or missing data (4/105).
      Table 1Baseline characteristics and patient demographics.
      Overall population

      N = 105
      Age, years
       Median (IQR)60.0 (54–67)
      Weight, kg
       Median (IQR)67.7 (59.4–77.1)
      History of hypertension, n (%)
       Yes52 (49.5)
       No53 (50.5)
      ECOG PS, n (%)
       066 (62.9)
       139 (37.1)
      FIGO stage at diagnosis, n (%)
       III82 (78.1)
       IV23 (21.9)
      Histological subtype at diagnosis, n (%)
       Serous100 (95.2)
       Endometrioid4 (3.8)
       Undifferentiated1 (1.0)
      Primary tumor site, n (%)
       Ovarian74 (70.5)
       Fallopian tube19 (18.1)
       Primary peritoneal12 (11.4)
      Debulking surgery, n (%)
       PDS39 (37.1)
       NACT/IDS66 (62.9)
      Postsurgery macroscopic residual disease, n (%)
      After PDS or IDS.
       Yes28 (26.7)
       No67 (63.8)
       Unknown10 (9.5)
      Response after surgery/platinum-based CT, n (%)
      After PDS or IDS.
      Investigator assessed.
       NED/CR61 (58.1)
       PR44 (41.9)
      HRD status, n (%)
       HRd49 (46.7)
      BRCAm29 (27.6)
      BRCAwt16 (15.2)
      BRCA unknown4 (3.8)
       HRp38 (36.2)
       HRnd
      Test inconclusive or failed or insufficient tissue.
      18 (17.1)
      BRCA status, n (%)
      BRCA status as determined by Myriad myChoice® HRD test performed on tumor tissue samples.
      BRCAm29 (27.6)
      BRCAwt67 (63.8)
       Not determined9 (8.6)
      Data are from the December 24, 2020, clinical cutoff date.
      Abbreviations: BRCAm, BRCA mutated; BRCAwt, BRCA wild-type; CR, complete response; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; FIGO, International Federation of Gynecology and Obstetrics; HRD, homologous recombination deficiency; HRd, homologous recombination deficient; HRnd, homologous recombination not determined; HRp, homologous recombination proficient; IDS, interval debulking surgery; IQR, interquartile range; NACT, neoadjuvant chemotherapy; NED, no evidence of disease; PDS, primary debulking surgery; PR, partial response.
      a After PDS or IDS.
      b Investigator assessed.
      c Test inconclusive or failed or insufficient tissue.
      d BRCA status as determined by Myriad myChoice® HRD test performed on tumor tissue samples.

      3.2 Progression-free survival

      For the primary analysis (data cutoff, December 24, 2020) the median time on study was 23.9 months (range, 0.5 to 33.7 months). Patients had received a median of 17 cycles of niraparib and 12 cycles of bevacizumab. The landmark PFS rates over time are shown in Fig. 2. In the overall population, the PFS rate at 18 months was 62% (95% CI 52–71%; Fig. 2A). The PFS rates at 18 months were 76% (95% CI 61–87%) in the HRd subgroup, 47% (95% CI 31–64%) in the HRp subgroup, and 56% (95% CI 31–79%) in the HRnd subgroup (Fig. 2B). When assessed by BRCA mutation status, the PFS rates at 18 months were 76% (95% CI 57–90%) in the BRCAm subgroup, 55% (95% CI 43–67%) in the BRCAwt subgroup, and 67% (95% CI 30–93%) in the BRCA not determined subgroup (Fig. 2C). In prespecified subgroup analyses, the PFS rate at 18 months in patients with no evidence of disease or a complete response following surgery and first-line platinum-based chemotherapy was 70% (95% CI 57–82%), compared with 50% (95% CI 35–65%) who experienced a partial response (Table 2).
      Fig. 2
      Fig. 2PFS rate over time in the overall population (A), by HRD status (B), and by BRCA mutation status (C). PFS rate was defined as the proportion of patients without disease progression or death within 6, 12, 18, or 24 months after initiation of niraparib plus bevacizumab combination maintenance therapy; disease progression was investigator-assessed according to RECIST v1.1. All results are from the December 24, 2020, clinical cutoff date.
      Abbreviations: BRCAm, BRCA mutated; BRCAunk, BRCA unknown; BRCAwt, BRCA wild type; HRd, homologous recombination deficient; HRnd, homologous recombination not determined; HRp, homologous recombination proficient; PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.
      Table 2Prespecified subgroup analyses for PFS.
      nPFS rate at 18 months,

      % (95% CI)
      PFS rate was defined as the proportion of patients without disease progression or death within 18 months after initiation of niraparib plus bevacizumab combination maintenance therapy; disease progression was investigator assessed according to RECIST v1.1. Confidence intervals are constructed using exact method.
      Median PFS

      (95% CI), months
      Kaplan-Meier estimated median PFS.
      Age, years
       <657263 (50–74)19.6 (16.5–24.8)
       ≥653361 (42–77)17.4 (8.8–NE)
      ECOG PS
       06661 (48–72)19.6 (14.2–25.1)
       13964 (47–79)19.9 (12.1–NE)
      FIGO stage at initial diagnosis
       III8263 (52–74)19.9 (16.0–NE)
       IV2357 (35–77)17.4 (11.2–25.1)
      Chemotherapy during first-line platinum regimen
       Neoadjuvant6659 (46–71)17.4 (14.2–22.1)
       Adjuvant3967 (50–81)22.3 (13.8–NE)
      Postoperative macroscopic visible residual disease
       All patients
      Yes2857 (37–76)16.9 (12.1–NE)
      No6761 (49–73)19.6 (13.8–25.1)
       Primary debulking surgery/adjuvant
      Yes863 (25–92)28.3 (5.6–NE)
      No2463 (41–81)19.6 (12.1–NE)
       Neoadjuvant chemotherapy/interval debulking surgery
      Yes2055 (32–77)16.6 (8.7–22.1)
      No4360 (44–75)19.9 (11.1–25.1)
      Response after surgery/platinum-based CT
       NED/CR6170 (57–82)22.1 (16.9–25.1)
       PR4450 (35–65)15.5 (8.7–NE)
      HRD status
       HRd4976 (61–87)28.3 (19.9–NE)
      BRCAm2976 (57–90)NE (19.3–NE)
      BRCAwt1675 (48–93)28.3 (12.1–NE)
       HRp3847 (31–64)14.2 (8.6–16.8)
       HRnd1856 (31–79)12.1 (8.0–NE)
      BRCA status
      BRCAm2976 (57–90)NE (19.3–NE)
      BRCAwt6755 (43–67)16.4 (11.0–19.9)
      BRCA not determined967 (30–93)22.1 (7.5–NE)
      Data from the December 24, 2020, clinical cutoff date.
      Abbreviations: BRCAm, BRCA mutated; BRCAwt, BRCA wild-type; CI, confidence interval; CR, complete response; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; FIGO, International Federation of Gynecology and Obstetrics; HRD, homologous recombination deficiency; HRd, homologous recombination deficient; HRnd, homologous recombination not determined; HRp, homologous recombination proficient; NE, not evaluated; NED, no evidence of disease; PFS, progression-free survival; PR, partial response; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.
      a PFS rate was defined as the proportion of patients without disease progression or death within 18 months after initiation of niraparib plus bevacizumab combination maintenance therapy; disease progression was investigator assessed according to RECIST v1.1. Confidence intervals are constructed using exact method.
      b Kaplan-Meier estimated median PFS.
      Another data cut was conducted to report mature median PFS and assess interim OS (June 16, 2021), at which time PFS data was 50.5% mature. This data cut increased the median follow-up time to 28.7 months (IQR, 23.9 to 32.5 months). In the overall population, the median PFS was 19.6 months (95% CI 16.5–25.1 months; Fig. 3A ). The median PFS was 28.3 months (95% CI 19.9–NE), 14.2 months (95% CI 8.6–16.8 months), and 12.1 months (95% CI 8.0–NE) in the HRd, HRp, and HRnd subgroups, respectively (Fig. 3B). The median PFS was not reached in patients with tumors that were BRCAm and 16.4 months (95% CI 11.0–19.9 months) in patients with tumors that were BRCAwt (Fig. 3C). Median TFST was 17.5 months (95% CI 14.5–20.7 months); median TSST was not estimable (95% CI 32.1, not estimable), and OS data were immature, with an event rate of 23.8% in the overall population.
      Fig. 3
      Fig. 3Kaplan-Meier estimated duration of PFS in the overall population (A), by HRD status (B), and by BRCA mutation status (C). Disease progression was investigator-assessed according to RECIST v1.1. All results are from the June 16, 2021, clinical cutoff date.
      Abbreviations: BRCAm, BRCA mutated; BRCAwt, BRCA wild type; HRd, homologous recombination deficient; HRnd, homologous recombination not determined; HRp, homologous recombination proficient; NE, not evaluated; PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.
      Fig. 3
      Fig. 3Kaplan-Meier estimated duration of PFS in the overall population (A), by HRD status (B), and by BRCA mutation status (C). Disease progression was investigator-assessed according to RECIST v1.1. All results are from the June 16, 2021, clinical cutoff date.
      Abbreviations: BRCAm, BRCA mutated; BRCAwt, BRCA wild type; HRd, homologous recombination deficient; HRnd, homologous recombination not determined; HRp, homologous recombination proficient; NE, not evaluated; PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.

      3.3 Safety

      At the time of the December 24, 2020, clinical cutoff date, reasons for niraparib discontinuation included adverse event (30/105), disease progression (37/105), and patient decision to discontinue study treatment (9/105; Fig. 1). For bevacizumab, reasons for discontinuation included adverse event (32/105), disease progression (16/105), and patient decision to discontinue study treatment (8/105; Fig. 1). No patients discontinued because of COVID-19–related infections or complications.
      Overall, 104 (99.0%) and 96 (91.4%) patients had experienced an adverse event determined by the investigator to be related to niraparib or bevacizumab, respectively, at the time of the December 24, 2020, clinical cutoff date (Table 3). Serious TRAEs occurred in 21 (20.0%) patients overall; serious TRAEs related to niraparib and bevacizumab were reported in 19 (18.1%) and 7 (6.7%) patients, respectively. TRAEs led to withdrawal of niraparib in 29 (27.6%) patients and of bevacizumab in 27 (25.7%) patients (Table 3). Overall, 91 (86.7%) patients experienced a TRAE leading to niraparib interruption, and 51 (48.6%) patients experienced a TRAE leading to bevacizumab infusion delay.
      Table 3Overall summary of treatment-related adverse events.
      Parameter, n (%)Overall

      N = 105
      Any TRAE105 (100.0)
       Niraparib related104 (99.0)
       Bevacizumab related96 (91.4)
      Any grade ≥ 3 TRAE84 (80.0)
       Niraparib related81 (77.1)
       Bevacizumab related54 (51.4)
      Any serious TRAE21 (20.0)
       Niraparib related19 (18.1)
       Bevacizumab related7 (6.7)
      Any TRAE leading to discontinuation of any study treatment42 (40.0)
       Discontinuation of niraparib29 (27.6)
       Discontinuation of bevacizumab27 (25.7)
      Any TRAE leading to study treatment interruption93 (88.6)
       Niraparib interruption91 (86.7)
       Niraparib dose reduction78 (74.3)
       Bevacizumab interruption2 (1.9)
       Bevacizumab infusion delay51 (48.6)
      Any TEAE leading to death0
      Data from the December 24, 2020, clinical cutoff date.
      Per protocol, investigators were required to provide a causality assessment regarding the relationship of the event with the study drug and/or study procedure for all adverse events. Events were considered treatment related if a causal relationship between the medicinal product (and/or study procedures) and the AE was a reasonable possibility.
      Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.
      The most common TRAEs of any grade overall (related to niraparib and/or bevacizumab) were thrombocytopenia (70.5%, 74/105), fatigue (57.1%, 60/105), and anemia (52.4%, 55/105) (Table 4). The most common any-grade TRAEs related to niraparib were thrombocytopenia (70.5%, 74/105), fatigue (55.2%, 58/105), and anemia (52.4%, 55/105). The most common any grade TRAEs related to bevacizumab were hypertension (47.6%, 50/105) and proteinuria (39.0%, 41/105). The most common grade 3 or worse TRAEs overall were thrombocytopenia (39.0%, 41/105), anemia (34.3%, 36/105), and hypertension (25.7%, 27/105; Table 4). One patient developed acute myeloid leukemia (AML) after 25 cycles of maintenance treatment, and 1 other patient developed myelodysplastic syndrome (MDS) after 32 cycles.
      Table 4Incidence of TRAEs.
      Event, n (%)
      Any-grade TRAE related to niraparib or bevacizumab occurring in ≥10% of patients.
      TRAEs in the overall population, N = 105
      Related to

      niraparib
      Related to

      bevacizumab
      Any TRAE
      Related to niraparib and/or bevacizumab (not mutually exclusive).
      Any gradeGrade ≥ 3Any gradeGrade ≥ 3Any gradeGrade ≥ 3
      Thrombocytopenia
      Includes, thrombocytopenia and platelet count decreased.
      74 (70.5)41 (39.0)23 (21.9)10 (9.5)74 (70.5)41 (39.0)
      Fatigue58 (55.2)9 (8.6)27 (25.7)4 (3.8)60 (57.1)9 (8.6)
      Anemia
      Includes anemia and hemoglobin decreased.
      55 (52.4)36 (34.3)17 (16.2)9 (8.6)55 (52.4)36 (34.3)
      Nausea52 (49.5)1 (1.0)19 (18.1)055 (52.4)1 (1.0)
      Hypertension37 (35.2)21 (20.0)50 (47.6)27 (25.7)51 (48.6)27 (25.7)
      Neutropenia
      Includes neutropenia and neutrophil count decreased.
      27 (25.7)13 (12.4)10 (9.5)5 (4.8)28 (26.7)13 (12.4)
      Headache25 (23.8)6 (5.7)27 (25.7)5 (4.8)32 (30.5)6 (5.7)
      Leukopenia
      Includes leukopenia, white blood cell count decreased, and eosinophil count decreased.
      23 (21.9)08 (7.6)024 (22.9)0
      Vomiting19 (18.1)1 (1.0)5 (4.8)019 (18.1)1 (1.0)
      Dyspnea16 (15.2)1 (1.0)8 (7.6)1 (1.0)16 (15.2)1 (1.0)
      Constipation14 (13.3)09 (8.6)015 (14.3)0
      Decreased appetite13 (12.4)03 (2.9)013 (12.4)0
      Stomatitis12 (11.4)4 (3.8)6 (5.7)2 (1.9)12 (11.4)4 (3.8)
      Arthralgia11 (10.5)2 (1.9)7 (6.7)013 (12.4)2 (1.9)
      Insomnia11 (10.5)2 (1.9)6 (5.7)011 (10.5)2 (1.9)
      Epistaxis9 (8.6)018 (17.1)020 (19.0)0
      Proteinuria4 (3.8)041 (39.0)5 (4.8)41 (39.0)5 (4.8)
      Data from the December 24, 2020, clinical cutoff date.
      Per protocol, investigators were required to provide a causality assessment regarding the relationship of the event with the study drug and/or study procedure for all adverse events. Events were considered treatment related if a causal relationship between the medicinal product (and/or study procedures) and the AE was a reasonable possibility.
      Abbreviations: AE, adverse event; TRAE, treatment-related adverse event.
      a Related to niraparib and/or bevacizumab (not mutually exclusive).
      b Any-grade TRAE related to niraparib or bevacizumab occurring in ≥10% of patients.
      c Includes, thrombocytopenia and platelet count decreased.
      d Includes anemia and hemoglobin decreased.
      e Includes neutropenia and neutrophil count decreased.
      f Includes leukopenia, white blood cell count decreased, and eosinophil count decreased.

      3.4 Patient-reported outcomes

      FOSI data showed that combination treatment with niraparib and bevacizumab did not negatively impact patient-reported quality of life scores (Supplementary Fig. S1).

      4. Discussion

      In the OVARIO study, in which niraparib was added to bevacizumab in first-line maintenance, 75% of the overall population remained progression-free at the 12-month landmark analysis. The results of the OVARIO study also indicated a PFS rate at 18 months of 62% and a median PFS of 19.6 months in the overall population of patients with primary advanced ovarian cancer. In OVARIO, approximately 80% of enrolled patients had stage III disease, 60% were treated with neoadjuvant chemotherapy and interval debulking surgery, and 40% had only a partial response after surgery and completion of platinum-based chemotherapy, indicating that many of the patients enrolled in OVARIO had more severe disease and were at higher risk for disease progression than those in previous PARP inhibitor studies [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Perol D.
      • Gonzalez-Martin A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ].
      When evaluated by HRD status, the PFS rate over time and median PFS duration in OVARIO were numerically higher in patients in the HRd subgroup than in the HRp subgroup and in the BRCAm subgroup compared with the BRCAwt subgroup. In this single-arm study, the efficacy of niraparib in combination with bevacizumab in the overall population and across all biomarker subgroups is consistent with the continuum of niraparib efficacy demonstrated in other trials such as PRIMA and NOVA. Of note, PFS data for the BRCA groups are not yet fully mature.
      Although the limitations of the OVARIO study include the inherent lack of a comparator arm and the relatively small number of patients in the various subgroup analyses, the results from OVARIO are still consistent with available clinical data showing the benefit of first-line maintenance therapy with niraparib and bevacizumab as single agents in patients with ovarian cancer. In the PRIMA/ENGOT-OV26/GOG-3012 clinical trial of first-line maintenance therapy in patients with primary advanced ovarian cancer who responded to first-line platinum-based chemotherapy, niraparib resulted in significantly longer PFS duration compared with placebo in the overall and the HRd populations [
      • Gonzalez-Martin A.
      • Pothuri B.
      • Vergote I.
      • DePont Christensen R.
      • Graybill W.
      • Mirza M.R.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ]. Consistent with the PARP inhibitor mechanism of action [
      • Konecny G.E.
      • Kristeleit R.S.
      PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions.
      ], the PFS benefits of niraparib maintenance therapy compared with placebo in PRIMA were greatest in patients with HRd or BRCAm tumors [
      • Gonzalez-Martin A.
      • Pothuri B.
      • Vergote I.
      • DePont Christensen R.
      • Graybill W.
      • Mirza M.R.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ]. As a single agent, the clinical benefit of bevacizumab first-line maintenance therapy in patients with primary advanced ovarian cancer is well established (see recent meta-analysis from Liu et al.) [
      • Liu S.
      • Kasherman L.
      • Fazelzad R.
      • Wang L.
      • Bouchard-Fortier G.
      • Lheureux S.
      • et al.
      The use of bevacizumab in the modern era of targeted therapy for ovarian cancer: a systematic review and meta-analysis.
      ], and bevacizumab maintenance therapy has been incorporated into treatment recommendations for patients who are considered at high risk for disease progression [
      • Ledermann J.A.
      • Raja F.A.
      • Fotopoulou C.
      • Gonzalez-Martin A.
      • Colombo N.
      • Sessa C.
      • et al.
      Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ].
      The combination of antiangiogenic agents targeting VEGF and PARP inhibitors for treating ovarian cancer was first evaluated in patients with recurrent platinum-sensitive ovarian cancer. The combination of cediranib and olaparib compared with olaparib alone demonstrated a median PFS of 17.7 months vs 9.0 months [
      • Liu J.F.
      • Barry W.T.
      • Birrer M.
      • Lee J.M.
      • Buckanovich R.J.
      • Fleming G.F.
      • et al.
      Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.
      ]. In the AVANOVA2 trial, treatment with niraparib plus bevacizumab demonstrated a statistically significant improvement in median PFS compared with treatment with a PARP inhibitor alone (11.9 months vs. 5.5 months) [
      • Mirza M.R.
      • Avall Lundqvist E.
      • Birrer M.J.
      • dePont Christensen R.
      • Nyvang G.B.
      • Malander S.
      • et al.
      Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial.
      ]. Subsequently, the randomized phase III PAOLA-1 trial demonstrated that the combination of olaparib plus bevacizumab resulted in a statistically significant increase in median PFS as compared to bevacizumab monotherapy first-line maintenance therapy in patients with advanced primary ovarian cancer whose tumors were HRd and/or BRCAm [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Perol D.
      • Gonzalez-Martin A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ]. The results from these studies suggested that combining PARP inhibitor and anti-VEGF agents may impact PFS.
      Although the single-arm design of OVARIO also precludes the direct assessment of the magnitude of the clinical benefit of combination niraparib plus bevacizumab maintenance therapy, and thus we cannot determine whether these therapies are truly additive, the results from OVARIO provide several important insights. First, the OVARIO patient population had a high incidence of poor prognostic factors at baseline and was at high risk for disease progression. Based on practice patterns, bevacizumab is primarily used in the first-line setting for patients with poor prognosis and a high risk of disease recurrence. The median PFS of 19.6 months in the OVARIO study supports the addition of niraparib to bevacizumab maintenance therapy in patients with advanced disease and a poor prognosis.
      The higher PFS rate at 18 months and longer median duration of PFS results in the HRd vs HRp and BRCAm vs BRCAwt subgroups in OVARIO were consistent with the PRIMA [
      • Gonzalez-Martin A.
      • Pothuri B.
      • Vergote I.
      • DePont Christensen R.
      • Graybill W.
      • Mirza M.R.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ] and PAOLA-1 [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Perol D.
      • Gonzalez-Martin A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ] subgroup analyses and the known activity of PARP inhibitors. While not exactly comparable to the tissue-based HRD test, mutations in germline homologous recombination repair genes were not shown to impact the efficacy of bevacizumab when combined with chemotherapy in a retrospective subgroup analysis of GOG-218 patients by Norquist, et al. [
      • Norquist B.M.
      • Brady M.F.
      • Harrell M.I.
      • Walsh T.
      • Lee M.K.
      • Gulsuner S.
      • et al.
      Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: an NRG oncology/gynecologic oncology group study.
      ]. Given the OVARIO study design, it is not possible to discern the specific effect of combination therapy by biomarker status. Additional studies will be needed to evaluate the magnitude of the impact of niraparib plus bevacizumab combination therapy across biomarker populations.
      In terms of overall safety and tolerability, the TRAE reported with niraparib plus bevacizumab combination therapy in OVARIO were generally consistent with the known safety profiles of each drug given as monotherapy. No new safety signals were observed with the combination. Also consistent with prior studies with combinations of PARP inhibitors and bevacizumab, the rate of treatment discontinuation for the combination therapy given in OVARIO was higher than for monotherapy. Safety datasets for niraparib and bevacizumab combination therapy are limited, and there are differences in the study populations, design, and reporting. For example, in AVANOVA-2, which enrolled patients with platinum-sensitive recurrent ovarian cancer, the incidence of grade ≥ 3 events of anemia (15% vs 18%) and thrombocytopenia (10% vs 12%) were generally similar between the niraparib plus bevacizumab and niraparib alone treatment arms [
      • Mirza M.R.
      • Avall Lundqvist E.
      • Birrer M.J.
      • dePont Christensen R.
      • Nyvang G.B.
      • Malander S.
      • et al.
      Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial.
      ]. The incidence of grade ≥ 3 neutropenia was higher with combination therapy than with niraparib alone (8% vs 2%) [
      • Mirza M.R.
      • Avall Lundqvist E.
      • Birrer M.J.
      • dePont Christensen R.
      • Nyvang G.B.
      • Malander S.
      • et al.
      Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial.
      ]. In OVARIO, 78.1% of patients started maintenance therapy with 200 mg based on body weight and platelet count. Overall, 2 patients in OVARIO developed AML or MDS. Because OVARIO participants received prior cytotoxic chemotherapy, more data are needed to better understand relatedness and the contribution of niraparib to these events. Hypertension is a known adverse event with bevacizumab [
      • Liu S.
      • Kasherman L.
      • Fazelzad R.
      • Wang L.
      • Bouchard-Fortier G.
      • Lheureux S.
      • et al.
      The use of bevacizumab in the modern era of targeted therapy for ovarian cancer: a systematic review and meta-analysis.
      ] and niraparib [
      • Moore K.N.
      • Mirza M.R.
      • Matulonis U.A.
      The poly (ADP ribose) polymerase inhibitor niraparib: management of toxicities.
      ] monotherapy. In AVANOVA-2, 21% of patients in the niraparib plus bevacizumab arm experienced grade ≥ 3 hypertension compared with no patients in the niraparib alone arm [
      • Mirza M.R.
      • Avall Lundqvist E.
      • Birrer M.J.
      • dePont Christensen R.
      • Nyvang G.B.
      • Malander S.
      • et al.
      Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial.
      ]. Within the caveats described above, these results are generally similar to the 27.5% of patients who experienced grade ≥ 3 events of hypertension in OVARIO. Of note, in OVARIO, approximately 50% of patients had a history of hypertension at enrollment, which may have contributed to the increased rate of events compared with other studies. Given these findings, the 200-mg once daily starting dose of niraparib would seem the most likely dose regimen for further study in potential future trials of niraparib plus bevacizumab with or without other drugs. Taken together, the PFS and safety data are promising and support the feasibility of niraparib in combination with bevacizumab as first-line maintenance therapy in patients with primary advanced ovarian cancer who have limited treatment options and a poor clinical prognosis.
      In summary, OVARIO was a single-arm phase II trial designed to evaluate the feasibility of combination niraparib plus bevacizumab first-line maintenance therapy. This study explored the efficacy and safety of maintenance treatment with a PARP inhibitor combined with an antiangiogenic agent following first-line, platinum-based therapy plus an antiangiogenic agent in patients with advanced ovarian cancer. In the overall population and across examined biomarker subgroups, the addition of niraparib to bevacizumab as a first-line maintenance therapy showed promising PFS results and an acceptable safety profile that was consistent with the known side effects of each drug as a monotherapy.

      Prior presentation

      Data were presented in part as an oral presentation at the Society of Gynecologic Oncology 2020 Annual Meeting on Women's Cancer, March 28–31, 2020, and as a poster at the Society of Gynecologic Oncology 2021 Annual Meeting on Women's Cancer, March 19–25, 2021 (virtual meeting), and the Heartland Association for Gynecologic Oncology 2021, September 17–18, 2021. Updated data were presented as an oral presentation at Society of Gynecologic Oncology 2022 Annual Meeting on Women's Cancer, March 18–21, 2022.

      Support

      This trial was funded by GlaxoSmithKline .

      Data sharing statement

      Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

      Clinical trial information

      Author contributions

      Conception and design: All authors.
      Provision of study materials or patients: All authors and study investigators.
      Collection and assembly of data: All authors.
      Data analysis and interpretation: Ping Wang.
      Manuscript writing: All authors.
      Final approval of manuscript: All authors.
      Accountable for all aspects of the work: Melissa Hardesty, Jimmy Belotte.

      Declaration of Competing Interest

      MMH reports honoraria from Clinical Care Operations and GlaxoSmithKline; and advisory board fees from AstraZeneca-Merck, Immunogen and GlaxoSmithKline.
      TCK reports consulting and speakers' bureau fees from GlaxoSmithKline.
      GSW reports she served as PI for a clinical trial for which the institute received payment for conducting the trial from Abbvie, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cascadian Therapeutics, Celgene, Celldex Therapeutics, Daiichi Sankyo Pharma, Dana Farber Cancer Institute, G1Therapeutics, Genentech, H3BioMedicine Inc., Hoffmann-LaRoche, ImmunoGen, Incyte, Innocrin Pharm, Jansen, Lilly, Macrogenics, Medivation, Merrimack, NanoString Technologies, Novartis, Nucana, Odonate Therapeutics, Pfizer, Seattle Genetics, Sermonix Pharm, Taiho Oncology, and Tesaro.
      EH reports institutional research grant from Tesaro/GSK, Abbvie, Acerta Pharma, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Arvinas, AtlasMedX, Black Diamond, Boehringer Ingelheim, Clovis, Compugen, Curis, CytomX, Dana Farber Cancer Inst, Deciphera, eFFECTOR Therapeutics, Ellipses Pharma, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, InvestisBio, Jacobio, Karyopharm, Leap Therapeutics, Lilly, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millenium, Molecular Templates, Myraid Genetic Labs, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Radius Health, Regeneron, Repertoire Immune Medicine, Rgenix, Roche/Genentech, SeaGen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, Zymeworks and institional consulting fees from Arcus, Arvinas, Black Diamond, Boehringer Ingelheim, CytomX, Dantari, Deciphera Pharmaceuticals, Eisai, H3 Biomedicine, iTeos, Janssen, Lilly, Loxo, Merck, Mersana, Novartis, Pfizer, Puma Biotechnology, Relay Therapeutics, Roche/Genentech, SeaGen, Silverback Therapeutics.
      ELF has nothing to disclose.
      JB is an employee of GlaxoSmithKline.
      EKK is a former employee of GlaxoSmithKline and reports stock and stock option ownership at the time of GSK employment.
      PW is an employee of GlaxoSmithKline.
      DG is an employee of GlaxoSmithKline.
      AC reports consulting fees from Tempus and advisory board fees from GlaxoSmithKline.
      HJG has nothing to disclose.
      GEK reports speaker bureau fees from AstraZeneca, Clovis, GlaxoSmithKline/Tesaro, and Myriad Genetics.
      RGM reports personal fees from Fujirebio Diagnostics Inc., and Humphries Pharmaceutical; and institutional grants from Angle Plc.
      DLR reports research contracts paid to her institution from Aravive, Arch Oncology, Celsion, Clovis, Deciphera, Fujifilm, GlaxoSmithKline, Harpoon, Karyopharm, Mersana, Plexxikon, Roche, Shattuck Labs, Syros, and Tesaro; honoraria fees from GOG Foundation; travel support from Tesaro; advisory board fees from AstraZeneca, Bayer, Deciphera, Foundation Medicine, Genentech, Mersana, and Tesaro/GlaxoSmithKline; and unpaid leadership as the vice chair of board of directors for National Ovarian Cancer Coalition .

      Acknowledgment

      Writing and editorial support, funded by GlaxoSmithKline (Waltham, MA, USA), were provided by Betsy C. Taylor, PhD, ISMPP CMPP™, and Jennifer Robertson, PhD, of Ashfield MedComms, an Ashfield Health company (Middletown, CT, USA).

      Appendix A. Supplementary data

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