Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev

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      Abstract

      Background

      PAOLA-1/ENGOT-ov25 (NCT02477644) is the first phase III trial to evaluate the efficacy and safety of a PARP inhibitor with bev as first-line (1L) maintenance therapy for advanced OC, regardless of BRCA1/2 mutation (BRCAm) status.

      Methods

      PAOLA-1 is a randomized, double-blind, international phase III trial. Eligible pts had newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid OC, fallopian tube or primary peritoneal cancer. Pts had received standard PCh plus bev and were in clinical complete or partial response. Pts were randomized (2:1) to olaparib tablets (300 mg bid for up to 24 months [m]) plus bev (15 mg/kg, d1, q3w, for 15 m including when combined with PCh) or placebo (pbo) plus bev, stratified by 1L treatment outcome and tumour BRCAm status. The primary endpoint was investigator-assessed progression-free survival in the intent-to-treat population (PFS; modified RECIST v1.1).

      Results

      TableLBA2_PR
      Median, monthsHR (95% CI)
      Olaparib armPlacebo armP value
      PFS, investigator-assessed (59% maturity) (n = 806)22.116.60.59 (0.49–0.72)
      P < 0.0001
      PFS by tBRCAm status* tBRCAm (n = 237)37.2 18.921.7 16.00.31 (0.20–0.47)
      Non-tBRCAm (n = 569)0.71 (0.58–0.88)
      PFS by HRD status HRD-positive
      * These were prespecified subgroup analyses. PFS by tBRCAm was analysed using the electronic case report form dataset and PFS by HRD status by the myChoice® HRD Plus assay dataset (Myriad Genetic Laboratories, Inc);
      HRD score ≥42 including pts with a tBRCAm;
      (n = 387) HRD-positive, non-tBRCA
      * These were prespecified subgroup analyses. PFS by tBRCAm was analysed using the electronic case report form dataset and PFS by HRD status by the myChoice® HRD Plus assay dataset (Myriad Genetic Laboratories, Inc);
      HRD score ≥42 excluding pts with a tBRCAm;
      (n = 152) HRD-negative/unknown
      § HRD score <42 or inconclusive, missing or failed test CI, confidence interval; HR, hazard ratio; HRD, homologous recombination deficiency; PFS2, time to second progression; tBRCAm, tumour BRCA1/2 mutation.
      (n = 419)
      37.2 28.1 16.917.7 16.6 16.00.33 (0.25–0.45) 0.43 (0.28–0.66) 0.92 (0.72–1.17)
      * These were prespecified subgroup analyses. PFS by tBRCAm was analysed using the electronic case report form dataset and PFS by HRD status by the myChoice® HRD Plus assay dataset (Myriad Genetic Laboratories, Inc);
      HRD score ≥42 including pts with a tBRCAm;
      HRD score ≥42 excluding pts with a tBRCAm;
      § HRD score <42 or inconclusive, missing or failed test CI, confidence interval; HR, hazard ratio; HRD, homologous recombination deficiency; PFS2, time to second progression; tBRCAm, tumour BRCA1/2 mutation.
      Grade ≥3 AEs were reported by 57% vs 51% of olaparib and pbo pts; the most common were hypertension (19% vs 30%) and anaemia (17% vs < 1%). There were five treatment emergent AEs of death (olaparib, n = 1; pbo, n = 4). Olaparib and pbo dose interruptions, reductions and discontinuations occurred in 54% vs 24%, 41% vs 7% and 20% vs 6% of pts, respectively. There was no clinically meaningful difference in health-related quality of life.

      Conclusions

      Addition of olaparib to bev maintenance therapy following 1L PCh plus bev led to a statistically significant and clinically meaningful PFS benefit in pts with advanced OC. The PFS benefit in pts with a tBRCAm and in HRD-positive pts was substantial.

      Clinical trial identification

      NCT02477644.

      Editorial acknowledgement

      Medical writing assistance was provided by Laura Smart, MChem, from Mudskipper Business, Ltd, funded by ARCAGY Research, AstraZeneca, and MSD.

      Legal entity responsible for the study

      ARCAGY Research.

      Funding

      ARCAGY Research, AstraZeneca, Merck & Co., Inc. and Hoffmann-La Roche Ltd.

      Disclosure

      I.L. Ray-Coquard: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Pharma Mar; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Genmab; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Pfizer. P. Pautier: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Genentech; Research grant / Funding (institution): PharmaMar. S. Pignata: Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Pfizer; Honoraria (self): Incyte; Honoraria (self): Novartis; Honoraria (self): PharmaMar; Honoraria (self): Clovis Oncology; Honoraria (self): Tesaro. D. Pérol: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): Eli-Lilly; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): BMS. A. González-Martín: Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: MSD; Advisory / Consultancy: Genmad. P. Sevelda: Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Amgen. K. Fujiwara: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Chugai Roche; Honoraria (self): Zeria; Honoraria (self): Taiho; Honoraria (self): Nihon Kayaku; Honoraria (self): Kyowahakko Kirin; Honoraria (self): Janssen; Honoraria (self): Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Kaken. I.B. Vergote: Advisory / Consultancy: Advaxis, Inc.; Advisory / Consultancy: Eisai, Inc.; Advisory / Consultancy: MSD, Belgium; Advisory / Consultancy: Roche NV; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genmab; Advisory / Consultancy: F. Hoffman-La Roche Ltd; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Millennium Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Clovis Oncology; Advisory / Consultancy: AstraZeneca NV; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Oncoinvent AS; Advisory / Consultancy, Travel / Accommodation / Expenses: Immunogen Inc.; Advisory / Consultancy: Sotio; Research grant / Funding (institution): Oncoinvent AS; Research grant / Funding (self): Amgen; Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Research grant / Funding (self): Stichting Tegen Kanker; Travel / Accommodation / Expenses: Takeda Oncology; Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: BIOCAD. N. Colombo: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BIOCAD; Honoraria (self), Advisory / Consultancy: Takeda. J. Mäenpää: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Advisory / Consultancy: Glovis. F. Selle: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: MSD France; Honoraria (self): PharmaMar; Honoraria (self), Travel / Accommodation / Expenses: Tesaro; Honoraria (self): Clovis Oncology; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Non-remunerated activity/ies: Post-university teaching. J. Sehouli: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Clovis Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Roche Diagnostics; Advisory / Consultancy: Merck; Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisei; Advisory / Consultancy: Johnson & Johnson; Advisory / Consultancy: MSD; Advisory / Consultancy: Novocure; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bristol-Myers Squibb. D. Lorusso: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy: Immunogen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Officer / Board of Directors: GCIG. E.M. Guerra Alia: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: V Simposio Grupo Español de Investigación en Cáncer de Ovario (GEICO); Travel / Accommodation / Expenses: Baxter; Speaker Bureau / Expert testimony: Sociedad Española de Nutrición (SENPE)Parenteral y Enteral. C. Lefeuvre-Plesse: Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Pfizer. U. Canzler: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Lilly. A. Lortholary: Honoraria (self): AstraZeneca; Honoraria (self): Tesaro. F. Marmé: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Tesaro; Honoraria (self): Clovis Oncology; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self): Celgene; Honoraria (self): Genomic Health; Honoraria (self), Advisory / Consultancy: PharmaMar; Honoraria (self): Amgen; Advisory / Consultancy: Curvac Celgene; Advisory / Consultancy: Curevac; Advisory / Consultancy: Vaccibody. E. Pujade-Lauraine: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer. P. Harter: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Sotio; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self): Stryker; Honoraria (self): ASCO; Honoraria (self): Zai Lab; Honoraria (self): MSD; Advisory / Consultancy: Lilly; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Immunogen; Advisory / Consultancy: MSD/Merck.