Studio retrospettivo di Real World sull’impiego di Olaparib in donne carriers di mutazione germline o somatica a carico dei geni BRCA1 o BRCA2, affette da recidiva platino sensibile di carcinoma ovarico

RAZIONALE Le pazienti arruolate nei trials clinici sono selezionate I dati sull’impiego Real Life di Olaparib in letteratura sono limitati Anemia e nausea sono gli eventi avversi più frequenti e la loro gestione non è ben codificata al di fuori dei trials clinici Pochi dati disponibili sulle modalità di riduzioni di dose in funzione della tossicità L’efficacia delle terapie somministrate dopo progressione al trattamento con Olaparib non è stata descritta

Olaparib Real World data First real life data on Olaparib in BRCA1/2 mutated Platinum-Sensitive relapsed EOC in France: analysis of 51 pts. 31 centres. May 2014-March 2015 Results: 14 pts (28.6%) treated >3 months 4 pts (8.2%) >6 months collection of safety data= ongoing 6 pts (11.8%) discontinued olaparib (3 pts for AE/ADRs+2 for PD+ 1 for aggravation of a previous leiomyosarcoma) 88% of pts still treated Un lavoro simile a quello che vi mostrerò a breve è stato pubblicato come abstract su european journal of cancer qualche mese fa . Gli autori descrivono un’esperienza multicentrica che ha coinvolto 31 centri in francia analizzando 52 pazienti recidivare in trattamento con olaparib da maggio 2014 a marzo 2015 nell’autorizzazione temporanea all’utilizzo del farmaco prima che entrasse in commercio. Olaparib è stato ben tollerato con 88% pazienti ancora in trattamento al momento della presentazione dei dati T. De La Motte Rouge et al, EJC sep. 2016 Volume 51, Supplement 3, Pages S548–S549

Olaparib prospective Real World trials C-PATROL Non-interventional study to collect clinical and patient reported outcome data in an olaparib treated BRCAm+ PSR ovarian cancer population. Purpose: obtain prospectively real-world effectiveness, safety and treatment patterns data of patients with BRCAm+, PSR ovarian cancer in German hospitals and outpatient practices treated with Olaparib. Study Population 300 patients in 80 sites (approx. 40 hospitals and 40 outpatient practices) in Germany. Study Start Date: October 2015 Estimated Study Completion Date: June 2021 https://clinicaltrials.gov/ct2/show/NCT02503436?term=real+life+olaparib&rank=1

Studio retrospettivo, multicentrico atto a descrivere e valutare la sicurezza e l’efficacia di Olaparib prescritto come monoterapia in indicazione dal gennaio 2015 ad ottobre 2017

OBIETTIVI DELLO STUDIO Valutare l’efficacia clinica nel mondo reale della monoterapia di mantenimento con Olaparib in termini di: End point primario Percentuale di pazienti in trattamento con olaparib per > 6 mesi e >12 mesi End point secondari Sopravvivenza libera da progressione (PFS) Tassi di risposte obiettive (ORR) e controllo di malattia (DCR) Sopravvivenza globale (OS) Descrivere la sicurezza del trattamento con Olaparib. Descrivere le modalità di gestione della nausea e dell’anemia. Descrivere le riduzioni di dose applicate in funzione della tossicità. Descrivere la terapia oncologica effettuata dopo la progressione e la sua efficacia.

OLAPARIB-REAL LIFE TRIAL Criteri di inclusione età >18 anni s/g BRCA1/2 mutate Recidiva di ca. ovarico platino-sensibile In RC o RP alla più recente terapia a base di platino Istologia sierosa di alto grado Olaparib capsule 400 mg b.i.d. Progressione e/o tossicità inaccettabile Trattamenti successivi Durata periodo osservazione: gennaio 2015 - ottobre 2017

real world experience in two Italian Cancer Centers Olaparib as maintenance treatment in relapsed platinum-sensitive BRCA mutated ovarian cancer: real world experience in two Italian Cancer Centers Materials and Methods Observational, retrospective study, carried out in two Italian Hospitals (National Cancer Institute of Naples and National Cancer Institute of Milan). Archival medical records of all the BRCA mutated relapsed ovarian cancer patients treated with olaparib in two Italian centers form September 1st, 2015 to March 14th, 2017 were analyzed. Primary endpoint To describe the percentage of patients that received olaparib for ≥6 months and ≥12 months. Secondary endpoints the description of objective response rate (ORR), disease control rate (DCR), PFS and safety Olaparib was administered according to the conventional schedule of 400 mg (eight 50 mg capsules) twice daily, equivalent to a total daily dose of 800 mg continuously

Monitoring flow-chart Olaparib 400mg p.o. b.i.d. Blood count Blood count Blood count Blood count Cycle 3 Cycle1 Cycle 2 D7 D15 D7 D15 Clinical examination, blood count routine biochemistry Radiologic assessment Ca125 Clinical examination, blood count routine biochemistry ECG

Demographic and baseline characteristics Age, median (range) 61 (44–79) Primary tumor type, n (%) Ovarian 21 (95.4) Fallopian tube 1 (4.6) Primary peritoneal FIGO stage at diagnosis, n (%) I-II 2 (9.1) III 18 (81.8) IV Prior treatment regimens, n (%) 2 lines 8 (36.4) 3 lines 9 (40.9) 4 lines ≥4 lines 3(13.6) Platinum-free interval, n (%) > 6 <12 months >12 months 14 (63.6) Response to platinum therapy, n (%) Complete response Partial response 12 (54.5) NA Archival medical records of all the BRCA mutated relapsed ovarian cancer patients treated with olaparib in two Italian centers form September 1st, 2015 to March 14th, 2017 were analyzed. Olaparib was administered according to the conventional schedule of 400 mg (eight 50 mg capsules) twice daily, equivalent to a total daily dose of 800 mg continuously Abbreviations: NA: not available Most of the patients (63.6%) were heavily pre-treated, with at least 3 or more lines of previous treatments

Demographic and baseline characteristics Type of BRCA mutations, n (%) Germline 21 (95.5) Somatic 1 (4.5) BRCA gene mutated, n (%) BRCA1 15 (68.2) BRCA2 7 (31.8)

Objective responses according to RECIST 1 Objective responses according to RECIST 1.1 and Ca-125 responses according to GCIG criteria Tumor Radiologically evaluable n (%) Yes No 12 (54.5) 10 (45.5) Best RECIST 1.1 response n (%) RP RC SD PD DCR (PR+CR+SD) 2 (16.7) 5 (41.6) 3 (25) 9 (75) Best Ca125 response GCIG criteria n (%)* 1 (11.2) 4 (44.4) ORR= 33.4% DCR= 75% *9 patients were evaluable for Ca-125 response. Abbreviations: CR: complete response; DCR: disease control rate; GCIG: Gynecological Cancer Intergroup; PD: progressive disease; PR: partial response; RECIST: Response Evaluation Criteria In Solid Tumors; SD: stable disease.

Efficacy results In our analysis about 55% of our patients were treated with the PARPi for ≥6 months, and 27.2% for ≥12 months. Moreover, 17 patients (77.3%) are still receiving the drug, and some of them started treatment just a few months ago. 21 out of 22 patients are still alive (95.4%) The very low rate of events didn’t allow us to evaluate PFS at this time point, suggesting a great impact of olaparib maintenance on the time of further re-treatment that will be later assessed in subsequent analysis. No significantly differences were founded between BRCA1 and BRCA2 mutated patients In the STUDY 19, at median follow-up of 5.9 years, about 45% of BRCA mutated patients received olaparib for ≥12 months.

Most common adverse events All grades n (%) Grade 1 Grade 2 Grade 3 /4 Nausea 17 (77.3) 12 (54.5) 3 (13.6) 2 (9.1) Fatigue 14 (63.6) 1(4.5) 1 (4.5) Anaemia 5 (22.7) Thrombocytopenia 4 (18.1) Leucopoenia 8 (36.4) Overall 7 (31.7) Nausea: 77.3% vs 73% (Phase II) and vs 75.9% (phase III studies) Fatigue: 63.3% vs 54% vs 65.6% Anemia: 54.5% vs 26% vs 43.6% These events occurred early during the treatment (within the first 4-8 weeks) and were mainly grade 1 or 2, generally transient and managed with supportive care without the need to change the dose. NCI CTC version 4.1

Dose reductions and interruptions Only patient interrupted olaparib due to sympromatic persistent G3 anemia Seven patients (31.8%) reduced Olaparib dose for: G3 nausea (57.1%); G3 haematologic (28.6%) and G2 fatigue (14.3%) NCI CTC version 4.1

Conclusions Our preliminary analysis suggests a good benefit/toxicity ratio of olaparib also in unselected population out of clinical trials. The need to evaluate the reproducibility of literature findings in heterogeneous patients require further studies.

L’unione fa la forza ! Dati Raccolti al 12.06.2017 TOTALE 65 PAZIENTI CENTRO n ° pazienti Bari INT “Giovanni Paolo II” 6 Università degli Studi di Bari Aldo Moro 9 Lecce Ospedale Vito Fazzi 13 Napoli Federico II 15 Totale 43 TOTALE 65 PAZIENTI

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