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Maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced high-grade ovarian cancer: Main analysis of second progression-free survival in the phase III PAOLA-1/ENGOT-ov25 trial

Open AccessPublished:September 03, 2022DOI:https://doi.org/10.1016/j.ejca.2022.07.022

      Highlights

      • We report the main second progression-free survival analysis of PAOLA-1.
      • Median second progression-free survival was significantly longer with olaparib + bevacizumab (bev) versus bev alone.
      • Addition of maintenance olaparib to bev provided benefit beyond first progression.
      • No new safety signals for olaparib were identified with longer follow-up.

      Abstract

      Background

      PAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. We report the prespecified main second progression-free survival (PFS2) analysis for PAOLA-1.

      Methods

      This randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were randomised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was reported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure.

      Results

      After a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64–0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64–0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymerase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab.

      Conclusion

      In newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevacizumab provided continued benefit beyond first progression, with a significant PFS2 improvement and a time to second subsequent therapy or death delay versus placebo plus bevacizumab.

      Graphical abstract

      Keywords

      1. Introduction

      Newly diagnosed, advanced ovarian cancer is treated with curative intent, with standard first-line therapy comprising cytoreductive surgery and platinum-based chemotherapy [
      • Colombo N.
      • Ledermann J.A.
      Updated treatment recommendations for newly diagnosed epithelial ovarian carcinoma from the ESMO Clinical Practice Guidelines.
      ]. Owing to late diagnosis, most patients have advanced disease and will relapse despite initial response to platinum-based chemotherapy [
      • 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 PAOLA-1/ENGOT-ov25 trial (NCT02477644) evaluated the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed, advanced ovarian cancer, irrespective of biomarker or surgical status, who were in clinical response after first-line platinum-based chemotherapy plus bevacizumab [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ]. Maintenance olaparib plus bevacizumab provided a significant progression-free survival (PFS) benefit versus placebo plus bevacizumab in the overall PAOLA-1 population (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.49–0.72; P < 0.001), with substantial benefit in patients who tested positive for homologous recombination deficiency (HRD; defined as a mutation in BRCA1 and/or BRCA2 [BRCAm] and/or genomic instability) (HR 0.33; 95% CI 0.25–0.45) [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ]. In response to these findings, the European Union, United States, and other countries approved maintenance olaparib plus bevacizumab in patients who test positive for HRD with advanced ovarian cancer in response to first-line platinum-based chemotherapy [
      AstraZeneca
      Lynparza 50 mg hard capsules summary of product characteristics.
      ,
      AstraZeneca
      LYNPARZA® (olaparib) tablets, for oral use: prescribing information.
      ,
      AstraZeneca
      Lynparza approved in Japan for the treatment of advanced ovarian, prostate and pancreatic cancers.
      ].
      Intermediate clinical end-points, those that occur after initial disease progression but before death, include time from randomisation to second progression or death (PFS2) and time from randomisation to second subsequent therapy or death (TSST) [
      • Matulonis U.A.
      • Oza A.M.
      • Ho T.W.
      • Ledermann J.A.
      Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials.
      ]. For clinical trials in settings where patients experience prolonged post-progression survival and receive numerous therapies after progression, the inclusion of intermediate end-points can further define efficacy and establish a better relationship between PFS and overall survival (OS) [
      • Matulonis U.A.
      • Oza A.M.
      • Ho T.W.
      • Ledermann J.A.
      Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials.
      ]. Intermediate end-points may provide supportive evidence for clinically meaningful PFS improvements and help to determine whether a treatment alters the cancer biology or affects the efficacy of subsequent therapies because resistance may have developed [
      • Matulonis U.A.
      • Oza A.M.
      • Ho T.W.
      • Ledermann J.A.
      Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials.
      ].
      We report the main PFS2 analysis of PAOLA-1 to describe the efficacy of maintenance olaparib plus bevacizumab versus placebo plus bevacizumab beyond first progression in newly diagnosed, advanced ovarian cancer.

      2. Materials and methods

      The methodology and results of the primary PFS analysis for PAOLA-1/ENGOT-ov25, including health-related quality of life data, have been previously reported [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ].

      2.1 Patients

      Eligible patients were aged ≥18 years with newly diagnosed, advanced (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV), high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer and/or fallopian tube cancer. Patients were eligible irrespective of surgical or biomarker status. Patients had no evidence of disease or clinical complete or partial response after first-line platinum-based chemotherapy plus bevacizumab. Full eligibility criteria are provided in the Appendix.

      2.2 Trial design

      PAOLA-1 was a randomised, double-blind, multicentre, phase III trial conducted in 11 countries. Randomisation was stratified according to first-line treatment outcome at screening and tumour BRCAm (tBRCAm) status. Patients were randomised 2:1 to olaparib tablets 300 mg twice daily or placebo twice daily. Trial interventions continued for up to 24 months or until investigator-assessed objective radiologic disease progression (modified Response Evaluation Criteria in Solid Tumours version 1.1 criteria [
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • Schwartz L.H.
      • Sargent D.
      • Ford R.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      ]) or unacceptable toxicity, whichever occurred first, as long as the patient experienced benefit and did not meet other discontinuation criteria. All patients received intravenous bevacizumab 15 mg/kg every 3 weeks for 15 months in total (including in combination with platinum-based chemotherapy).

      2.3 End-points

      The primary end-point was time from randomisation until investigator-assessed disease progression or death (PFS). Secondary end-points included PFS2 (a key secondary end-point included in the preplanned hierarchical-testing procedure; Fig. 1A), OS, time from randomisation to first subsequent therapy or death (TFST) and TSST. Data for adverse events (AEs) of special interest (AESIs) were collected beyond the treatment period and 30-day safety follow-up: myelodysplastic syndromes (MDS), acute myeloid leukaemia (AML), and new primary malignancies (NPMs).
      Fig. 1
      Fig. 1Schematic of the PFS2 and TSST end-points in the PAOLA-1 trial (A) and hierarchical-testing procedure for primary and key secondary endpoints (B). In the schematic in A, second disease progression occurs before initiation of the second subsequent therapy; however, the timing and order of these events is not fixed and varies between patients. PFS, progression-free survival; PFS2, time from randomisation to second progression or death; OS, overall survival; TSST, time from randomisation to second subsequent therapy or death.
      The primary PFS data cut-off (DCO) was 22 March 2019. The prespecified main PFS2 analysis was planned for approximately 53% data maturity (approximately 411 events) or 1 year after the PFS analysis (22 March 2020). Tumour HRD status was determined by myChoice® HRD Plus assay (Myriad Genetic Laboratories, Inc., Salt Lake City, UT, USA), with tBRCAm and/or a genomic instability score of ≥42 indicating a positive test. Methodology for the assessment of disease progression and trial oversight is available in the Appendix.

      2.4 Statistical analysis

      Efficacy data were summarised and analysed in the intent-to-treat population – all randomised patients. We used the electronic case report form analysis set, except for analyses by HRD status, where the Myriad data set was used. Safety data were summarised in the safety analysis set – all randomised patients who received ≥1 dose of olaparib or placebo. Secondary efficacy end-points were estimated using the Kaplan–Meier method and stratified log-rank tests. HRs and CIs were estimated from stratified Cox proportional hazards models. A hierarchical-testing procedure controlled for type 1 error at 5%, with PFS, PFS2, and OS tested in that order. Each subsequent end-point was tested if the previous end-point's null hypothesis was rejected (Fig. 1B). PFS2 subgroup analyses were conducted using unstratified Cox proportional hazards models, with subgroups defined post hoc.

      3. Results

      From July 2015 to September 2017, 806 patients were randomised; 535 of 537 patients assigned to olaparib plus bevacizumab and 267 of 269 patients assigned to placebo plus bevacizumab received the trial intervention (Fig. S1) [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ]. Baseline characteristics were balanced between trial groups (Table S1). Overall, 30% of patients had a tBRCAm and 48% were HRD positive. A poly(ADP-ribose) polymerase (PARP) inhibitor was first subsequent therapy in 9% and 27% of patients with olaparib plus bevacizumab and placebo plus bevacizumab, respectively (Table 1). In total, 82 patients were unblinded to their treatment allocation – 27 between randomisation and the primary DCO, and 55 between the primary and main PFS2 DCOs.
      Table 1First subsequent therapy after the randomised intervention.
      First subsequent therapy,
      Patients could receive >1 first subsequent therapy in combination; categories are not mutually exclusive.
      n (%)
      Olaparib plus bevacizumab (N = 537)Placebo plus bevacizumab (N = 269)
      PARP inhibitor
      Of the 121 patients who received a PARP inhibitor as a first subsequent therapy, 119 (98%) received PARP inhibitor maintenance therapy and 2 (2%) received PARP inhibitor treatment.
      49 (9)72 (27)
      Bevacizumab41 (8)27 (10)
      Platinum-based regimen273 (51)159 (59)
      Non-platinum-based regimen295 (55)183 (68)
      Intent-to-treat population.
      PARP, poly(ADP-ribose) polymerase.
      a Patients could receive >1 first subsequent therapy in combination; categories are not mutually exclusive.
      b Of the 121 patients who received a PARP inhibitor as a first subsequent therapy, 119 (98%) received PARP inhibitor maintenance therapy and 2 (2%) received PARP inhibitor treatment.
      The main PFS2 analysis was performed after 424 of 806 patients had PFS2 events (data maturity 53%; DCO 22 March 2020). Median PFS2 follow-up was 35.5 months (interquartile range 31.8–41.2) with olaparib plus bevacizumab and 36.5 months (32.3–39.9) with placebo plus bevacizumab. PFS2 duration was statistically significantly longer with olaparib plus bevacizumab than with placebo plus bevacizumab (median 36.5 months versus 32.6 months; HR 0.78; 95% CI 0.64–0.95; P = 0.0125) (Fig. 2).
      Fig. 2
      Fig. 2Kaplan–Meier estimates of investigator-assessed PFS2. Intent-to-treat population. Kaplan–Meier estimates of the rate of freedom from second disease progression, as assessed by investigators, and from death are shown. CI, confidence interval; HR, hazard ratio; PFS2, time from randomisation to second progression or death.
      In patients with HRD-positive tumours, including tBRCAm, median PFS2 was 50.3 months with olaparib plus bevacizumab and 35.3 months with placebo plus bevacizumab (HR 0.56; 95% CI 0.41–0.77) (Fig. 3A). In patients with HRD-positive tumours, excluding tBRCAm, median PFS2 was 50.3 months with olaparib plus bevacizumab and 30.1 months with placebo plus bevacizumab (HR 0.60; 95% CI 0.38–0.96) (Fig. 3B). In both HRD-positive subgroups, median PFS2 with olaparib plus bevacizumab was unstable due to the low number of events (including tBRCAm: 85 of 255; excluding tBRCAm: 41 of 97) and few patients at risk when the medians were reached. In patients with HRD-negative tumours or unknown HRD status, median PFS2 was 26.3 months with olaparib plus bevacizumab and 28.1 months with placebo plus bevacizumab, with no difference between treatments (HR 0.98; 95% CI 0.77–1.27) (Fig. 3C). In patients with HRD-negative tumours, excluding those with unknown HRD status, median PFS2 was 24.4 months with olaparib plus bevacizumab and 26.4 months with placebo plus bevacizumab, with no difference between treatments (HR 1.04; 95% CI 0.77–1.42) (Fig. S2C).
      Fig. 3
      Fig. 3Kaplan–Meier estimates of investigator-assessed PFS2 according to biomarker status. Subgroups were defined post hoc for analysis of PFS2. HRD status was determined for 82% of tumour samples. BRCAm, BRCA1 and/or BRCA2 mutation; CI, confidence interval; HR, hazard ratio; HRD, homologous recombination deficiency; PFS2, time from randomisation to second progression or death.
      In patients with a tBRCAm, median PFS2 was not reached with olaparib plus bevacizumab versus 45.0 months with placebo plus bevacizumab (HR 0.53; 95% CI 0.34–0.83) (Fig. S2A). In patients without a tBRCAm, median PFS2 was 29.2 months with olaparib plus bevacizumab and 28.5 months with placebo plus bevacizumab (HR 0.86; 95% CI 0.70–1.08) (Fig. S2B). Subgroup analyses showed a consistent PFS2 benefit with olaparib plus bevacizumab relative to placebo plus bevacizumab except for patients with HRD-negative tumours, with greatest benefit observed in patients with HRD-positive tumours (with or without a tBRCAm) or at lower clinical risk (Fig. 4).
      Fig. 4
      Fig. 4Subgroup analyses of PFS2. Subgroups were defined post hoc for analysis of PFS2. For the HRs, the size of the circle is proportional to the number of events. The grey band represents the 95% CI for the intent-to-treat population and the dashed line indicates the point of no effect. Tumour HRD status was determined by the Myriad myChoice® HRD Plus assay, with tBRCAm and/or a genomic instability score of ≥42 indicating a positive test. a Defined as those with FIGO stage III disease who had undergone upfront surgery and had residual disease or who had received neoadjuvant chemotherapy, or FIGO stage IV patients [
      • Harter P.
      • Mouret-Reynier M.A.
      • Pignata S.
      • Cropet C.
      • González-Martín A.
      • Bogner G.
      • et al.
      Efficacy of maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed, advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.
      ]; b Defined as those with FIGO stage III disease who had undergone upfront surgery and had complete resection [
      • Harter P.
      • Mouret-Reynier M.A.
      • Pignata S.
      • Cropet C.
      • González-Martín A.
      • Bogner G.
      • et al.
      Efficacy of maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed, advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.
      ]; c With two modalities, HRD-negative and HRD-unknown categories are merged; d With three modalities, HRD-negative and HRD-unknown categories are separate; e tBRCAm status according to the Myriad myChoice® HRD Plus assay. CI, confidence interval; eCRF, electronic case report form; FIGO International Federation of Gynecology and Obstetrics; HR, hazard ratio; HRD, homologous recombination deficiency; PFS2, time from randomisation to second progression or death; tBRCAm, tumour BRCA1 and/or BRCA2 mutation.
      Median TSST was 38.2 months with olaparib plus bevacizumab and 31.5 months with placebo plus bevacizumab (HR 0.78; 95% CI 0.64–0.95; P = 0.0115) (Fig. 5).
      Fig. 5
      Fig. 5Kaplan–Meier estimates of TSST. Intent-to-treat population. ∗P-value not adjusted for multiplicity. CI, confidence interval; HR, hazard ratio; TSST, time from randomisation to second subsequent therapy or death.
      In patients with HRD-positive tumours, median TSST was not reached with olaparib plus bevacizumab and was 35.2 months with placebo plus bevacizumab (HR 0.48; 95% CI 0.35–0.66). In patients with HRD-negative tumours or unknown HRD status, median TSST was 27.1 months with olaparib plus bevacizumab and 29.1 months with placebo plus bevacizumab (HR 1.05; 95% CI 0.82–1.36). In patients with tBRCAm, median TSST was not reached with olaparib plus bevacizumab and was 45.1 months with placebo plus bevacizumab (HR 0.48; 95% CI 0.31–0.75). In patients with non-tBRCAm, median TSST was 29.1 months with olaparib plus bevacizumab and 29.1 months with placebo plus bevacizumab (HR 0.87; 95% CI 0.70–1.08). OS data are currently immature (data maturity, 38%).
      The median duration of randomised treatment with the study intervention was 17.3 months (range 0.03–35.8) with olaparib plus bevacizumab and 15.6 months (0.07–27.6) with placebo plus bevacizumab. The safety profile of olaparib plus bevacizumab was consistent with the primary DCO [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ]. AEs are summarised in Tables S2 and S3. Generally, patients managed AEs by dose modifications. At the primary DCO, MDS/AML/aplastic anaemia (AA) occurred in 6 of 535 (1%) patients receiving olaparib plus bevacizumab and in 1 of 267 (0.4%) patients receiving placebo plus bevacizumab [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ]. There was one new case of AML with olaparib plus bevacizumab at the main PFS2 DCO (total incidence remained at 1%; Table 2). With placebo plus bevacizumab, an additional three patients developed AML at the main PFS2 DCO (total incidence 1%). In total, three of the four patients in the placebo plus bevacizumab group who developed MDS/AML/AA received a PARP inhibitor as first subsequent maintenance treatment before onset of AML. At the primary DCO, NPMs occurred in 6 of 535 (1%) patients receiving olaparib plus bevacizumab and in 3 of 267 (1%) receiving placebo plus bevacizumab [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ]. At the main PFS2 DCO, additional NPMs occurred in seven patients receiving olaparib plus bevacizumab (total incidence 2%) and two receiving placebo plus bevacizumab (total incidence 2%). At the main PFS2 DCO, the incidence of NPMs was 4% in patients with tBRCAm and 2% in patients without tBRCAm with olaparib plus bevacizumab, compared with 3% in patients with tBRCAm and 2% in patients without tBRCAm with placebo plus bevacizumab (Table 2). At the primary DCO, pneumonitis/interstitial lung disease/bronchiolitis occurred in 6 (1%) patients receiving olaparib plus bevacizumab and no patients receiving placebo plus bevacizumab [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ], with no additional cases in either treatment group at the main PFS2 DCO.
      Table 2AESIs in the safety analysis set and by tBRCAm status.
      Patients with a tBRCAmPatients without a tBRCAmSafety analysis set
      Olaparib plus bevacizumab (N = 157)Placebo plus bevacizumab (N = 80)Olaparib plus bevacizumab (N = 380)Placebo plus bevacizumab (N = 189)Olaparib plus bevacizumab (N = 535)Placebo plus bevacizumab (N = 267)
      MDS/AML/AA, n (%)3 (2)1 (1)4 (1)3 (2)7 (1)4 (1)
      Three of the four patients in the placebo plus bevacizumab group who developed MDS/AML/AA received a PARP inhibitor as first subsequent maintenance treatment before onset of AML.
      NPMs, n (%)6 (4)2 (3)7 (2)3 (2)13 (2)
      At primary PFS analysis, NPMs in the olaparib plus bevacizumab group were breast cancer (n = 2; tBRCAm: n = 1; non-tBRCAm: n = 1), lung cancer (n = 1; tBRCAm), myeloma (n = 1; non-tBRCAm), squamous skin cancer (n = 1; non-tBRCAm) and pancreatic cancer (n = 1; tBRCAm), and in the placebo plus bevacizumab group were breast cancer (n = 2; tBRCAm: n = 1; non-tBRCAm: n = 1) and thyroid cancer (n = 1; non-tBRCAm). Additional NPMs reported at main PFS2 analysis in the olaparib plus bevacizumab group were breast cancer (n = 5; tBRCAm: n = 2; non-tBRCAm: n = 3), squamous skin cancer (n = 1; non-tBRCAm) and colon cancer (n = 1; tBRCAm), and in the placebo plus bevacizumab group were breast cancer (n = 1; non-tBRCAm) and malignant neoplasm (n = 1; tBRCAm).
      5 (2)
      At primary PFS analysis, NPMs in the olaparib plus bevacizumab group were breast cancer (n = 2; tBRCAm: n = 1; non-tBRCAm: n = 1), lung cancer (n = 1; tBRCAm), myeloma (n = 1; non-tBRCAm), squamous skin cancer (n = 1; non-tBRCAm) and pancreatic cancer (n = 1; tBRCAm), and in the placebo plus bevacizumab group were breast cancer (n = 2; tBRCAm: n = 1; non-tBRCAm: n = 1) and thyroid cancer (n = 1; non-tBRCAm). Additional NPMs reported at main PFS2 analysis in the olaparib plus bevacizumab group were breast cancer (n = 5; tBRCAm: n = 2; non-tBRCAm: n = 3), squamous skin cancer (n = 1; non-tBRCAm) and colon cancer (n = 1; tBRCAm), and in the placebo plus bevacizumab group were breast cancer (n = 1; non-tBRCAm) and malignant neoplasm (n = 1; tBRCAm).
      Pneumonitis/ILD/bronchiolitis, n (%)1 (0.6)0 (0)5 (1)0 (0)6 (1)0 (0)
      Electronic case report form analysis set used for tBRCAm assignment.
      AA, aplastic anaemia; AESI, adverse event of special interest; AML, acute myeloid leukaemia; ILD, interstitial lung disease; MDS, myelodysplastic syndromes; NPM, new primary malignancy; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PFS2, time from randomisation to second progression or death; tBRCAm, tumour BRCA1 and/or BRCA2 mutation.
      a Three of the four patients in the placebo plus bevacizumab group who developed MDS/AML/AA received a PARP inhibitor as first subsequent maintenance treatment before onset of AML.
      b At primary PFS analysis, NPMs in the olaparib plus bevacizumab group were breast cancer (n = 2; tBRCAm: n = 1; non-tBRCAm: n = 1), lung cancer (n = 1; tBRCAm), myeloma (n = 1; non-tBRCAm), squamous skin cancer (n = 1; non-tBRCAm) and pancreatic cancer (n = 1; tBRCAm), and in the placebo plus bevacizumab group were breast cancer (n = 2; tBRCAm: n = 1; non-tBRCAm: n = 1) and thyroid cancer (n = 1; non-tBRCAm). Additional NPMs reported at main PFS2 analysis in the olaparib plus bevacizumab group were breast cancer (n = 5; tBRCAm: n = 2; non-tBRCAm: n = 3), squamous skin cancer (n = 1; non-tBRCAm) and colon cancer (n = 1; tBRCAm), and in the placebo plus bevacizumab group were breast cancer (n = 1; non-tBRCAm) and malignant neoplasm (n = 1; tBRCAm).

      4. Discussion

      The addition of maintenance olaparib to bevacizumab provided continued benefit beyond first progression, with a statistically significant PFS2 improvement versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. The substantial PFS2 benefit with olaparib plus bevacizumab was seen in patients with HRD-positive tumours, regardless of tBRCAm status. The PFS2 improvement was supported by a delay in TSST with olaparib plus bevacizumab versus placebo plus bevacizumab. No new safety signals were observed for olaparib plus bevacizumab with longer-term follow-up.
      These data provide supportive evidence that clinically meaningful PFS improvements with olaparib plus bevacizumab compared with placebo plus bevacizumab, as reported by Ray-Coquard et al. [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ], persist beyond first progression and throughout subsequent lines of therapy. This is supported by a delay in TSST and suggests the addition of olaparib to bevacizumab did not negatively affect the efficacy of subsequent therapy. While OS data remain immature (currently 38% data maturity), the intermediate clinical end-points PFS2 and TSST can help to further define the efficacy of maintenance olaparib plus bevacizumab in this population and establish a better relationship between PFS and OS. The secondary efficacy findings we report for olaparib plus bevacizumab in PAOLA-1 align with those reported for olaparib with longer-term follow-up in the SOLO1 trial in newly diagnosed, advanced ovarian cancer with a BRCAm [
      • Banerjee S.
      • Moore K.N.
      • Colombo N.
      • Scambia G.
      • Kim B.G.
      • Oaknin A.
      • et al.
      Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]. In updated post hoc analyses after 5 years’ SOLO1 follow-up, olaparib provided a PFS2 benefit compared with placebo (HR 0.46; 95% CI 0.33–0.65), which was supported by delays in TFST (HR 0.33; 95% CI 0.25–0.44) and TSST (HR 0.46; 95% CI 0.34–0.63) with olaparib [
      • Banerjee S.
      • Moore K.N.
      • Colombo N.
      • Scambia G.
      • Kim B.G.
      • Oaknin A.
      • et al.
      Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.
      ].
      Subgroup analyses showed a PFS2 benefit with olaparib plus bevacizumab in patients with HRD-positive tumours (with or without a BRCAm) and those with a tBRCAm, agreeing with the PFS benefit reported in the primary analysis [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ]. Analyses showed a PFS2 benefit with olaparib plus bevacizumab in most subgroups and particularly in patients aged ≥65 years, those with FIGO stage IV disease and those at lower clinical risk. Harter and colleagues [
      • Harter P.
      • Mouret-Reynier M.A.
      • Pignata S.
      • Cropet C.
      • González-Martín A.
      • Bogner G.
      • et al.
      Efficacy of maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed, advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.
      ] reported a PFS benefit in patients at lower (HR 0.46; 95% CI 0.30–0.72) and higher (HR 0.60; 95% CI 0.49–0.74) clinical risk in post hoc analyses of PAOLA-1 data from the primary DCO.
      The safety profile of maintenance olaparib plus bevacizumab remained consistent with that seen at the primary DCO, with most AEs either grade 1 or 2 and managed by dose modifications. No additional cases of MDS/AML/AA were reported during longer-term follow-up in SOLO1 [
      • Banerjee S.
      • Moore K.N.
      • Colombo N.
      • Scambia G.
      • Kim B.G.
      • Oaknin A.
      • et al.
      Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]. With longer follow-up in PAOLA-1, only one new case was reported in the olaparib plus bevacizumab group, and a total of three cases in the placebo plus bevacizumab group who received a PARP inhibitor as first subsequent maintenance treatment, providing additional reassurance regarding the risk of MDS/AML/AA in the newly diagnosed setting. Compared with the primary DCO, there was a small increase in NPMs with both treatments; similar to SOLO1 [
      • Banerjee S.
      • Moore K.N.
      • Colombo N.
      • Scambia G.
      • Kim B.G.
      • Oaknin A.
      • et al.
      Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.
      ], the incidence was balanced between treatment arms. Although there was a slightly higher incidence of NPMs overall in patients receiving olaparib plus bevacizumab with a tBRCAm than in those without a tBRCAm, of the seven patients receiving olaparib plus bevacizumab who developed breast cancer, only three (43%) had a tBRCAm.
      The PAOLA-1 trial limitations have been described in full by Ray-Coquard et al. [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Pérol D.
      • González-Martín A.
      • Berger R.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ] and include the lack of an olaparib monotherapy comparator arm. There are methodological and clinical limitations to PFS2 and TSST. While PFS2 was a key secondary end-point included in the multiple-testing procedure, it was assessed by the investigator based on radiological, clinical or CA125 progression without further collection and independent reading of scans and without mandating the scan frequency in order to follow routine clinical practice. The effects of trial interventions on PFS2 can be confounded by effective subsequent-line therapies (including use of PARP inhibitors as a first subsequent therapy) and by mortality unrelated to cancer or its treatment. PFS2 is assessed in the cohort who has experienced first disease progression and, by definition, excludes those free from first disease progression or death and who would be considered to have an optimal response to treatment. Furthermore, if a treatment is associated with longer PFS than a comparator, the cohorts in which PFS2 is assessed may be unbalanced in terms of their numbers and characteristics. TSST may be influenced by the investigator, the patient and their relationship. Decisions about chan-ging therapy should account for various factors, including tumour burden, tolerability, AEs and availability of alternative treatments.

      5. Conclusions

      The addition of maintenance olaparib to bevacizumab provided continued benefit beyond first progression, with a statistically significant PFS2 improvement versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. The substantial PFS2 benefit with olaparib plus bevacizumab was seen in patients who were HRD positive, regardless of tBRCAm status. There were no new safety signals for olaparib plus bevacizumab with longer-term follow-up, including AML and MDS.

      Author contributions

      Conceptualisation and methodology: IR-C; Investigation and resources: AG-M, CD, IV, NC, YT, UC, CZ, EMG-A, CBL, FM, FB, NdG, ND, PAF, GS, MJR-P, CCo, PP, IR-C; Formal analysis: CCr; Writing – original draft: AG-M, CD, FH, CCr, PG, RB, HO, IV, NC, MRM, YT, UC, CZ, EMG-A, CBL, FM, FB, NdG, ND, PAF, GS, MJR-P, TM, CCo, PP, IR-C; Writing – review and editing: AG-M, CD, FH, CCr, PG, RB, HO, IV, NC, MRM, YT, UC, CZ, EMG-A, CBL, FM, FB, NdG, ND, PAF, GS, MJR-P, TM, CCo, PP, IR-C.

      Conflict of Interest statement

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
      Antonio González-Martín reports advisory/consultancy fees from Alkermes , Amgen , AstraZeneca , Clovis Oncology , Genmab, GSK, ImmunoGen , MSD, MacroGenics , Novartis , Oncoinvent, Pfizer / Merck , PharmaMar , Roche , SOTIO, Sutro Biopharma; speaker bureau fees from AstraZeneca , PharmaMar , Roche , GSK, Clovis Oncology ; research grant/funding from Roche and Tesaro; and travel/accommodation expenses from AstraZeneca , PharmaMar , Roche , Tesaro.
      Christophe Desauw reports honoraria (institution) from MSD; and travel grants from Pfizer and Merck.
      Florian Heitz reports honoraria from Roche, AstraZeneca , Clovis Oncology , GSK; advisory/consultancy fees from Roche, Novocure , Amedes, GSK; research grant/funding from AstraZeneca ; and travel grants from AstraZeneca , Tesaro, Roche , PharmaMar .
      Claire Cropet reports no conflicts of interest.
      Piera Gargiulo reports no conflicts of interest.
      Regina Berger reports no conflicts of interest.
      Hiroyuki Ochi reports no conflicts of interest.
      Ignace Vergote reports consultancy fees from Agenus, Aksebio, Amgen (Europe) GmbH, AstraZeneca , Bristol-Myers Squibb , Clovis Oncology , Carrick Therapeutics , Deciphera Pharmaceuticals , Eisai , Elevar Therapeutics, Roche , Genmab, GSK, ImmunoGen, Jazz Pharmaceuticals, Karyopharm, Mersana Therapeutics, Takeda, MSD, Novocure, Novartis, Octimet Oncology NV, Oncoinvent, OncXerna Therapeutics, Sanofi, Seagen, SOTIO, Verastem Oncology, Zentalis; contracted research funding (via KU Leuven) from Oncoinvent and Genmab; research grants from Amgen and Roche ; and travel/accommodation expenses from Amgen, MSD, Tesaro, AstraZeneca , Roche .
      Nicoletta Colombo reports research grants from AstraZeneca , PharmaMar, Roche ; honoraria for lectures from AstraZeneca , Tesaro, Novartis, Clovis Oncology, MSD, GSK, Eisai; honoraria for advisory boards from Roche , PharmaMar, AstraZeneca , Clovis Oncology, MSD, GSK, Tesaro, Pfizer, BIOCAD, ImmunoGen, Mersana Therapeutics, Eisai, OncXerna Therapeutics; and is a steering committee member on ESMO clinical guidelines and a scientific committee chair for Acto Onlus.
      Mansoor R. Mirza reports research grants from AstraZeneca , Ultimovacs, Apexigen, GSK; speaker fees from AstraZeneca and GSK; advisory board fees from AstraZeneca , GSK, Karyopharm, Nuvation Bio, Roche , Zai Lab, Merck, BIOCAD, Boehringer Ingelheim; member of board of directors at Karyopharm and Sera Prognostics; stock/share ownership at Karyopharm and Sera Prognostics; and study chair at Deciphera and Mersana Therapeutics.
      Youssef Tazi reports no conflicts of interest.
      Ulrich Canzler reports advisory fees from AstraZeneca ; and speaker’ bureau fees from Lilly and AstraZeneca .
      Claudio Zamagni reports personal grants/contracts from Eisai, PharmaMar, Lilly, Celgene, MSD, GSK, Amgen, Daiichi Sankyo; personal and institutional grants/contracts from Roche , Novartis, AstraZeneca , Pfizer, Tesaro, Pierre Fabre, Istituto Gentili, Teva, Seagen; advisory board fees from Roche , Eisai, Novartis, AstraZeneca , Pfizer, PharmaMar, Amgen, Tesaro, QuintilesIMS, Lilly, Celgene, MSD, GSK, Daiichi Sankyo; travel/meetings support from Roche , Novartis, Pfizer, PharmaMar, Tesaro, Pierre Fabre, Istituto Gentili, Celgene; and other financial or non-financial interests relating to Roche , Novartis, AstraZeneca , Pfizer, Amgen, Tesaro, QuintilesIMS, MSD, GSK, Daiichi Sankyo.
      Eva M. Guerra-Alia reports consulting fees from AstraZeneca -MSD, Clovis Oncology, GSK-Tesaro, PharmaMar, Roche ; speaker bureau/expert testimony honorarium from AstraZeneca -MSD, PharmaMar, Roche , GSK-Tesaro, Clovis Oncology; and travel support from Roche , GSK-Tesaro, Baxter.
      Charles B. Levaché reports honoraria (institution) from Isofol, AstraZeneca , Pfizer, Roche , Bristol Myers Squibb, Amgen.
      Frederik Marmé reports honoraria from AGO research GmbH (funding indirectly provided by AstraZeneca ); and personal fees from Roche , AstraZeneca , Pfizer, Tesaro, Novartis, Amgen, PharmaMar, Genomic Health, CureVac, Eisai, Clovis Oncology, Janssen-Cilag, Gilead, GSK, MSD, Seagen, Myriad Genetics, Pierre Fabre.
      Fernando Bazan reports advisory/consultancy fees from AstraZeneca , Novartis, Pfizer, Clovis Oncology; and speaker bureau fees from AstraZeneca , Novartis, Pfizer, Clovis Oncology.
      Nikolaus de Gregorio reports advisory fees from AstraZeneca , Roche , GSK, MSD, Myriad Genetics; and travel expenses from AstraZeneca .
      Nadine Dohollou reports grants/research support from AstraZeneca , Bristol Myers Squibb, Boehringer Ingelheim, Genomic Health, Lilly, MSD, Novartis, Pfizer, Roche ; consultancy fees from Daiichi Sankyo, Lilly, Roche , Seagen; and conference fees from Daiichi Sankyo, Lilly, Roche , Seagen.
      Peter A. Fasching reports grants/research support from BioNTech, Pfizer, Cepheid; speaker/advisory board fees from Novartis, Pfizer, Daiichi Sankyo, AstraZeneca , Eisai, MSD, Lilly, Pierre Fabre, Seagen, Roche , Agendia, Sanofi, Gilead.
      Giovanni Scambia reports grants/research support from MSD; consulting fees from Johnson & Johnson and Tesaro; and speaker bureau fees from Clovis Oncology and MSD.
      Maria J. Rubio-Pérez reports no conflicts of interest.
      Tsveta Milenkova reports full-time employment with AstraZeneca and AstraZeneca stock ownership.
      Cristina Costan reports advisory/consultancy fees from AstraZeneca , Seagen, Daiichi Sankyo.
      Patricia Pautier reports honoraria (self) from AstraZeneca and PharmaMar; honoraria (institution) from GSK, MSD, Roche , Bristol Myers Squibb; advisory/consulting fees (institution) from Onxeo, PharmaMar, Clovis Oncology, GSK, AstraZeneca ; research grant/funding (institution) from PharmaMar and Onxeo; and travel support from AstraZeneca , Roche , MSD.
      Isabelle Ray-Coquard reports honoraria (self) from Agenus, Blueprint Medicines, Bristol Myers Squibb, PharmaMar, Genmab, Pfizer, AstraZeneca , Roche , GSK, MSD, Deciphera, Mersana Therapeutics, Merck Sereno, Novartis, Amgen, MacroGenics, Tesaro, Clovis Oncology; honoraria (institution) from GSK, MSD, Roche , Bristol Myers Squibb; advisory/consulting fees from AbbVie, Agenus, Advaxis, Bristol Myers Squibb, PharmaMar, Genmab, Pfizer, AstraZeneca , Roche /Genentech, GSK, MSD, Deciphera, Mersana Therapeutics, Merck Sereno, Novartis, Amgen, Tesaro, Clovis Oncology; research grant/funding (self) from MSD, Roche , Bristol Myers Squibb; research grant/funding (institution) from MSD, Roche , Bristol Myers Squibb, Novartis, AstraZeneca , Merck Sereno; and travel support from Roche , AstraZeneca , GSK.

      Role of funding source

      This work was supported by ARCAGY Research, AstraZeneca , Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) and F. Hoffmann-La Roche . ARCAGY Research contributed to the study design; the collection, analysis and interpretation of data; writing the study report; and in the decision to submit the article for publication. AstraZeneca , MSD, and F. Hoffmann-La Roche provided input into data interpretation and AstraZeneca provided input into writing the study report. Medical writing assistance was provided by Anna Campbell, PhD, CMPP, of Cence, funded by AstraZeneca and MSD.

      Acknowledgements

      The authors thank the patients who participated in this trial and their families.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Colombo N.
        • Ledermann J.A.
        Updated treatment recommendations for newly diagnosed epithelial ovarian carcinoma from the ESMO Clinical Practice Guidelines.
        Ann Oncol. 2021; 32: 1300-1303
        • 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.
        Ann Oncol. 2013; 24: vi24-vi32
        • Ray-Coquard I.
        • Pautier P.
        • Pignata S.
        • Pérol D.
        • González-Martín A.
        • Berger R.
        • et al.
        Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
        N Engl J Med. 2019; 381: 2416-2428
        • AstraZeneca
        Lynparza 50 mg hard capsules summary of product characteristics.
        2021
        • AstraZeneca
        LYNPARZA® (olaparib) tablets, for oral use: prescribing information.
        2021
        • AstraZeneca
        Lynparza approved in Japan for the treatment of advanced ovarian, prostate and pancreatic cancers.
        2020
        • Matulonis U.A.
        • Oza A.M.
        • Ho T.W.
        • Ledermann J.A.
        Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials.
        Cancer. 2015; 121: 1737-1746
        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • Schwartz L.H.
        • Sargent D.
        • Ford R.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Harter P.
        • Mouret-Reynier M.A.
        • Pignata S.
        • Cropet C.
        • González-Martín A.
        • Bogner G.
        • et al.
        Efficacy of maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed, advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.
        Gynecol Oncol. 2022; 164: 254-264
        • Banerjee S.
        • Moore K.N.
        • Colombo N.
        • Scambia G.
        • Kim B.G.
        • Oaknin A.
        • et al.
        Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2021; 22: 1721-1731