Ovarian cancer: more women benefit from maintenance combined targeted therapy

Barcelona, Spain, 28 September 2019 - New data presented at the ESMO Congress 2019 in Barcelona, Spain, (1) show the benefit of a more intensive maintenance regimen for ovarian cancer with the PARP inhibitor olaparib added to bevacizumab, in an all-comers population, with and without a BRCA mutation. According to late breaking results of the PAOLA-1/ENGOT-ov25 trial, this approach extends progression free survival in patients with advanced ovarian cancer. (2)

Ovarian cancer is the fifth most common cancer in women and the most lethal gynaecological tumour. The majority of patients are diagnosed in an advanced stage and despite responding well to first-line treatment, usually relapse less than two years after diagnosis. Longer progression free survival after first-line therapy improves the probability of response to a new line of chemotherapy. The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone.

PAOLA-1/ENGOT-ov25 is the first phase III trial to examine the efficacy and safety of a PARP inhibitor with bevacizumab as first-line maintenance therapy in patients with ovarian cancer with and without a BRCA mutation. This international, academic-led trial enrolled 806 patients with stage III/IV ovarian cancer and partial or complete response to standard platinum-based chemotherapy and bevacizumab. After completing first-line chemotherapy, patients were randomly allocated 2:1 to olaparib or placebo, both on top of bevacizumab. They received olaparib for up to 24 months and bevacizumab for 15 months in total. The primary outcome was investigator-assessed progression free survival.

The median follow-up was 24 months in the olaparib arm and 22.7 months in the placebo arm. Median progression free survival was 22.1 months in the olaparib group and 16.6 months in the placebo group (hazard ratio 0.59; 95% confidence interval 0.49-0.72; p<0.0001).

"This study reports the greatest hazard ratio (0.59) and longest progression free survival we have ever seen," said study author Prof Isabelle Ray-Coquard, Centre Leon Berard, Universite Claude Bernard, Lyon, and president of the GINECO group France. "Patient selection was not restricted by surgical outcome or BRCA mutation status, so participants represent the general population of women with advanced ovarian cancer. Previous studies of relapse have suggested benefits from combining anti-angiogenic agents and PARP inhibitors (3,4) and today's results appear to support this. In addition, olaparib did not increase side-effects compared to placebo."

In prespecified subgroup analyses, the progression free survival benefit of olaparib versus placebo was even more pronounced in patients with a BRCA mutation and in those with homologous recombination deficiency (HRD), with hazard ratios of 0.31 and 0.33, respectively. Median progression free survival with olaparib reached 37.2 months in patients with a BRCA mutation and in patients with HRD. "The results in HRD patients without a BRCA mutation identify, for the first time, a patient population with greater clinical benefit from olaparib when added to bevacizumab," said Ray-Coquard.

Ray-Coquard noted that randomisation in PAOLA-1/ENGOT-ov25 started a median six weeks after the last cycle of chemotherapy, whereas most previous trials started randomisation with the first cycle of chemotherapy. "It is an important point to consider when comparing the results to other data," she said.

Commenting on the relevance of the data, Dr Ana Oaknin, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, said: "The main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low. The combination of bevacizumab and olaparib as maintenance therapy should become a new standard of care for patients with advanced ovarian cancer. The PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy, but this is a small group. This trial is a significant step forward in treatment for these women."

Other positive trials of PARP inhibitors in advanced ovarian cancer are presented at the ESMO Congress 2019. In the PRIMA trial, niraparib administered after completion of first-line chemotherapy significantly improved progression free survival. (5) In the VELIA/GOG-3005 trial, veliparib integrated with first-line chemotherapy then continued as maintenance treatment significantly extended progression free survival regardless of response to first-line treatment. (6)

Oaknin said these three trials and the SOLO-1 trial, (7) all integrating PARP inhibitors in first-line treatment, are a milestone for patients. "After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression free survival and hopefully we will improve long-term outcome," she said. Oaknin noted there were important differences between the two trials and PAOLA-1/ENGOT-ov25. For example, patients in PRIMA did not receive bevacizumab, were not stratified according to BRCA status, and were treated for almost three years. The VELIA trial tested veliparib concurrent with standard chemotherapy and then as maintenance therapy. "Therefore, comparisons between clinical trials should be made with caution due to their intrinsic differences," she said.

Regarding the next priority for research in this field, Oaknin said: "The five-year overall survival for ovarian cancer is around 45% and we need strategies to improve that figure. I think the next approach is to incorporate immunotherapy as part of first-line therapy. Ongoing trials are expected to report in two to three years."

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References

1 https://www.esmo.org/Conferences/ESMO-Congress-2019?hit=ehp

2 LBA2_PR 'Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (prs) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev' will be presented by Isabelle L. Ray-Coquard during the Presidential Symposium I on Saturday, 28 September, 16:30 to 18:20 (CEST) in the Barcelona Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019

3 Mirza MR, Avall Lundqvist E, Birrer MJ, et al. Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. Lancet Oncol. 2019. pii: S1470-2045(19)30515-7. doi: 10.1016/S1470-2045(19)30515-7.

4 Liu JF, Barry WT, Birrer M, et al. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. Ann Oncol. 2019;30:551-557. doi: 10.1093/annonc/mdz018.

5 LBA1 'Niraparib treatment in patients with newly diagnosed advanced ovarian cancer (OC)' will be presented by A. Gonzalez Martin during the Presidential Symposium I on Saturday, 28 September, 16:30 to 18:20 (CEST) in the Barcelona Auditorium (Hall 2).

6 LBA3 'VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)'will be presented by Robert L. Coleman during the Presidential Symposium I on Saturday, 28 September, 16:30 to 18:20 (CEST) in the Barcelona Auditorium (Hall 2).

7 Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2018; 379:2495-2505. doi: 10.1056/NEJMoa1810858

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LBA2_PR - 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

I.L. Ray-Coquard1, P. Pautier2, S. Pignata3, D. Perol4, A. Gonzalez-Martin5, P. Sevelda6, K. Fujiwara7, I.B. Vergote8, N. Colombo9, J. Maenpaa10, F. Selle11, J. Sehouli12, D. Lorusso13, E.M. Guerra Alia14, C. Lefeuvre-Plesse15, U. Canzler16, A. Lortholary17, F. Marme18, E. Pujade-Lauraine19, P. Harter20

1 Medical Oncology, Centre Leon Berard, Lyon, France, 2Gynecologie Medicale, Gustave Roussy, Villejuif, France, 3Istituto Nazionale Tumori, Naples and IRCCS, MITO, Naples, Italy, 4Centre Leon Berard, Lyon and GINECO, France, 5Clinica Universidad de Navarra, Madrid, Spain, 6Krankenhaus Hietzing; Abteilung Gynakologie, Vienna, and AGO Au, Austria, 7Saitama Medical University, Saitama and GOTIC, Japan, 8Gynaecology, Belgian Gynecologic Oncology Group (BGOG) and University of Leuven, Leuven, Belgium, 9Gynecologic Cancer Program, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy, 10Tampere University and University Hospital, Tampere and NSGO, Finland, 11Service D'oncologie Medicale, Groupe Hospitalier Diaconesses-Croix Saint Simon, Paris, France, 12Department Of Gynecology, Universitatsklinik Charite, Campus Virchow Klinikum, Berlin, Germany, 13Gynecologic Oncology, Ovarian Cancer/Mario Negri Gynecologic Oncology (MITO/MaNGO), Fondazione IRCCS National Cancer Institute, Milan, Italy, 14Hospital Universitario Ramon y Cajal, Madrid and GEICO, Spain, 15Centre Eugene Marquis, Rennes and GINECO, France, 16Gynecology, University Hospital Carl Gustav Carus Dresden, Dresden, Germany, 17Centre Catherine de Sienne Hopital prive du Confluent, Nantes and GINECO, France, 18Gynecologic oncology, University Hospital Mannheim, Mannheim, Germany, 19Medical Oncology, Clinical Research, ARCAGY-GINECO, Paris, France, 20Kliniken Essen Mitte, Essen and AGO, Germany

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: 537 pts were randomized to olaparib plus bev and 269 to pbo plus bev. Pt characteristics were well balanced. Median follow-up was 24.0 m in the olaparib arm and 22.7 m in the pbo arm. PFS was significantly increased in the olaparib arm. PFS2 is immature.

Grade greater than equal to 3 AEs were reported by 57% vs 51% of olaparib and pbo pts; the most common were hypertension (19% vs 30%) and anaemia (17% v <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 Roche.

Legal entity responsible for the study: ARCAGY Research

Funding: ARCAGY Research, AstraZeneca and Roche

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. Maenpaa: 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. Marme: 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.

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