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Olaparib nel trattamento della recidiva BRCAmutata di carcinoma ovarico

Olaparib nel trattamento della recidiva BRCAmutata di carcinoma ovarico. Sabrina Chiara Cecere. Vanda Salutari. Oncologia Medica Uro-Ginecologica IRCCS - Fondazione “G. Pascale ” Napoli. Ginecologia oncologica Policlinico A. Gemelli Roma. Ovarian cancer: not unique disease.

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Olaparib nel trattamento della recidiva BRCAmutata di carcinoma ovarico

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  1. Olaparib nel trattamento della recidiva BRCAmutata di carcinoma ovarico Sabrina Chiara Cecere Vanda Salutari Oncologia Medica Uro-Ginecologica IRCCS - Fondazione “G. Pascale” Napoli Ginecologia oncologica Policlinico A. Gemelli Roma

  2. Ovarian cancer: not unique disease

  3. Selected genomic alterations and their frequencies in high-grade serous ovarian Konstantinopulos PA, et al Cancer Discovery 2015 TCGA Consortium. Nature 2011;Turner, et al. Nat Rev Cancer 2004; Patch, et al, Nature 2015

  4. Prevalence of BRCA mutations in ovariancancer • Approximately 50% of HGSOCs exhibit genetic or epigenetic alterations of HR pathway genes. • GermlineBRCA1 and BRCA2 mutations are the most common alterations, and are present in: • 14–15% of all EOCs • 22.6% of HGSOCs • Somatic BRCA1 and BRCA2 mutations have been identified in 6-7% of HGSOCs • Up to 44% have no family history Konstantinopulos PA, et al Cancer Discovery 2015

  5. PARP Inhibition May Result in Tumor Cell Death via Multiple Pathways, in HRD Deficient and Platinum Sensitive Tumors

  6. PARP Inhibitors

  7. Olaparib indications: US vs Europe US approval: PAST: Olaparib monotherapy in patient with germline mutated BRCA OC who have received > 3 or more chemotherapy treatments together with a companion diagnsostic test (BRCA analysis CDx). 1 PRESENT: maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. European approval: Olaparib monotherapy for the maintenance treatment of adult patient with platinum-sensitive relapsed BRCA-mutated (Germline/somatic) OC, high grade sereous, fallopian tube, or primary peritoneal cancer who are in response (compleate or partial) to platinum-based chemotherapy. 2 From February 2018 Lynparza is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy 1. Kaufman B, et al. J ClinOncol 2015 . 2. Ledermann J et al. New Engl J Med 2012

  8. Study 19: Phase II trial design, endpoints and BRCA testing Primary endpoint: Progression-free survival (PFS)by RECIST 1.0 Secondary endpoints included:Overall survival (OS), safety and tolerability Exploratory endpoints: Time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST) • N=265 • ‘Platinum-sensitive’ recurrent high-grade serous ovarian cancer • ≥2 prior regimens of platinum-based chemotherapy • Complete or partial response to most recent platinum-based regimen n=136 Olaparib maintenance monotherapy (400 mg bid, capsules) Double-blind randomization 1:1 Treatment until progression Placebo (bid, capsules) n=129 • BRCA testing: • Previous local germlineBRCA testing (case report forms) • Retrospective germlineBRCA testing or tumour BRCA testing BRCAm: n=136 BRCAwt:* n=118 *BRCAwt patients did not have a detected BRCAm or had a BRCAm of unknown significance bid, twice daily; BRCAwt, BRCA1/2 wild type; RECIST, Response Evaluation Criteria in Solid Tumors

  9. Study 19: Progression free survival results Statistically significant improvement in progression-free survival with olaparib1,2 PFS Overall population: Median PFS (olaparib vs placebo): 8.4 months vs 4.8 months HR=0.35, P<0.0001 BRCAm subgroup: Median PFS (olaparib vs placebo): 11.2 months vs 4.3 months HR=0.18, P<0.0001

  10. Study 19 OS analyses 28 Aug 2008 31 Oct 2011 30 Sep 2015 26 Nov 2012 DCO DCO DCO FSI 3 OS data maturity: 77% Alpha (two-sided) = 0.95% Additional follow-up since previous analysis = 3 years 2 1 OS data maturity: 38% Alpha (two-sided) = 0.1% HR=0.94 95% CI 0.63–1.39, P=0.751 OS data maturity: 58% Alpha (two-sided) = 3% HR=0.88 95% CI 0.64–1.21, P=0.442 CI, confidence interval; DCO, data cut-off; FSI, first subject in . Ledermann J et al. New Engl J Med 2012;366:1382–1392; 2. Ledermann J et al. Lancet Oncol 2014;15:852–861 Jonathan A Ledermann at ASCO 2016

  11. Final analysis of the long-term benefit of olaparib in pts with PSR SOC in Study 19 79% data maturity DCO, median OS follow-up was 78.0 months CI, confidence interval; DCO, data cut-off; FSI, first subject in . Ledermann J et al. New Engl J Med 2012;366:1382–1392; 2. Ledermann J et al. Lancet Oncol 2014;15:852–861 Jonathan A Ledermann at ASCO 2017

  12. Long-term exposure to treatment Charlie Gourley, et al 2017 ASCO Meeting

  13. SOLO-1, -2, -3Randomizedphase III studies of Olaparib in OC

  14. SOLO2/ENGOT-Ov21: study design • Patients • BRCA1/2 mutation • Platinum-sensitive relapsed ovarian cancer • At least 2 prior lines of platinum therapy • CR or PR to most recent platinum therapy Olaparib tablets 300 mg bid n=196 Randomized 2:1 Primary endpoint Investigator-assessed PFS Placebo n=99 • Sensitivity analysis: PFS by blinded independent central review (BICR) • Key secondary endpoints: • Time to first subsequent therapy or death (TFST), time to second progression (PFS2), time to second subsequent therapy or death (TSST), overall survival (OS) • Safety, health-related quality of life (HRQoL*) *Primary endpoint for HRQoL was trial outcome index (TOI) of the FACT-O (Functional Assessment of Cancer Therapy – Ovarian) Presented by Pujade-Lauraineat SGO 2017 annual meeting

  15. Demographic and baseline characteristics Presented by Pujade-Lauraine at SGO 2017 annual meeting

  16. PFS by investigator assessment 100 90 80 70 60 Olaparib 50 Progression-free survival (%) 40 30 Placebo 20 10 5.5 19.1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months since randomization No. at risk Olaparib Placebo 196 99 182 70 156 37 134 22 118 18 104 17 89 14 82 12 32 7 29 6 3 0 2 0 0 0 Median follow-up was 22.1 months in the olaparib group and 22.2 months for placebo Presented by Pujade-Lauraine at SGO 2017 annual meeting

  17. PFS sensitivity analysis using BICR 100 90 80 70 60 Olaparib 50 Progression-free survival (%) 40 30 Placebo 20 10 5.5 30.2 0 0 3 6 9 12 15 18 21 24 27 30 33 Months since randomization No. at risk Olaparib Placebo 196 99 176 62 148 26 128 18 112 16 103 14 88 14 82 11 30 6 28 5 3 0 1 0 Presented by Pujade-Lauraine at SGO 2017 annual meeting

  18. Subgroup analysis of PFS Olaparib better Placebo better Presented by Pujade-Lauraineat SGO 2017 annual meeting

  19. Secondary efficacy endpoints Time to first subsequent therapy, or death (TFST) 27.9 7.1 Median not reached PFS2 18.4 Time to second subsequent therapy, or death (TSST) Not reached Median not reached 18.2 Olaparib Data immature Overall survival Placebo 0 10 20 30 Median (months) Presented by Pujade-Lauraine at SGO 2017 annual meeting

  20. Total adverse events AE, adverse event; SAE, serious adverse event Presented by Pujade-Lauraine at SGO 2017 annual meeting

  21. Most common hematologicadverse events MDS/AML: 4 cases in olaparib group (2.1%), including one case of CMML 4 cases in placebo group (4.0%) Presented by Pujade-Lauraineat SGO 2017 annual meeting *Grouped terms

  22. Most common non-hematologic adverse events 2.6 4.1 2.0 2.6 1.0 Olaparib Placebo 1.0 Nausea 75.9 33.3 Fatigue/asthenia 65.6 39.4 All grades (frequency ≥20%) 0.5 Vomiting 37.4 19.2 2.6 3.0 Diarrhea Grade ≥3 (frequency ≥2.5%) 32.8 20.2 Dysgeusia 26.7 7.1 3.0 Headache 25.1 13.1 Abdominal pain 24.1 31.3 Decreased appetite 22.1 11.1 Constipation 20.5 23.2 Adverse events (%) 100 75 50 25 0 0 25 50 75 100 Other AEs of interest Elevated ALT: 10 patients in olaparib group (5.1%) vs 4 patients in placebo group (4.0%) Elevated AST: 4 patients in olaparib group (2.1%) vs 4 patients in placebo group (4.0%) Presented by Pujade-Lauraine at SGO 2017 annual meeting

  23. Health-related quality of life: TOI of the FACT-O Estimated difference in adjusted means = −0.03 (95% CI −2.19 to 2.13, P=0.98) TOI, trial outcome index; FACT-O, Functional Assessment of Cancer Therapy – Ovarian Presented by Pujade-Lauraine at SGO 2017 annual meeting

  24. Olaparib in first line:SOLO-1 Phase III trial- BRCAm population only First-line maintenance Olaparib 300mg os bid • 344 patients • PFS/PFS2/OS + QoL Randomization 2:1 Response to platinum-based chemotherapy Placebo

  25. Olaparib in first line: PAOLA 1 study design

  26. Unsolved questions on HRD and PARP inhibitors

  27. Study 19: Progression free survival results

  28. Why do some HRD negative casesrespond to platinum and to PARPi? The test can miss some HRD positive cases? HRD tumours are more prevalent than previously believed in serous high grade? Other non HRD DNA repair impaired mechanisms in these patients?

  29. Why do some HRD negative casesrespond to platinum and to PARPi? The test can miss some HRD positive cases? HRD tumours are more prevalent than previously believed in serous high grade? Other non HRD DNA repair impaired mechanisms in these patients?

  30. Why some HRD negative casesrespond to platinum and toPARPi?Does the test miss some HRD positive cases? • Specificityisnot 100% • Basalheterogeneity • Prospectivegeneticinstability? ENGOT-OV16/NOVA Trial discussed by Sandro Pignata Chien J et al Front Oncol 2013 Barbara Norquist at 2017 ASCO Annual Meeting

  31. HRD is more frequentthanpreviouslybelieved?Does the testing show all the HRD mechanisms? Konstantinopulos PA, et al Cancer Discovery 2015 TCGA Consortium. Nature 2011;Turner, et al. Nat Rev Cancer 2004; Patch, et al, Nature 2015

  32. Comparing the toxicity of PARP inhibitors

  33. GI toxicities are common with all PARP inhibitors (% pts) GI toxicities are common with all PARP inhibitors (% of pts) Presented By Kathleen Moore at 2017 ASCO Annual Meeting

  34. Hematologictoxicities Hematologic toxicities Presented By Kathleen Moore at 2017 ASCO Annual Meeting

  35. Additional toxicities that appear to differ between agents <br /> Presented By Kathleen Moore at 2017 ASCO Annual Meeting Presented By Kathleen Moore at 2017 ASCO Annual Meeting

  36. QoL !!!!!

  37. WHAT ABOUT RECHALLENGE?

  38. Perspectives for PARP INHIBITION WHAT ABOUT RECHALLENGE? • Combinations : Olaparib + immuno check point inhibitors • Resistant disease: Wee-1 inhibitors + Olaparib (phase 1)

  39. Resistence to PARP inhibitors

  40. Presented By Kathleen Moore at 2017 ASCO Annual Meeting

  41. Samples from individual with germline BRCA 2 mutation 10 years after initial diagnosis after multiple chemotherapeutic regimens for recurrent disease, including a poly (ADP-ribose) polymerase (PARP) inhibitor Norquist M, et al JCO 2011

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