Manuel Rodrigues

PARP inhibitors as maintenance therapy in ovarian cancer after platinum-sensitive recurrence: real-world experience from the Unicancer network

Abstract Background Based on results of randomized clinical trials, polyADP-ribose polymerase inhibitors (PARPi) have become the standard of care in patients with platinum-sensitive recurrent ovarian cancer (OvC) in patients responding to platinum chemotherapy. However, little is known about their impact on survival in a real-world setting. Patients and methods This retrospective French multicenter observational study included women with platinum-sensitive recurrent OvC (not limited to the first platinum-sensitive relapse) receiving PARPi as maintenance after response to platinum-based chemotherapy. They were compared to patients with similar characteristics undergoing observation after chemotherapy completion. Data were collected in the Ovarian Cancer Epidemiological Strategy and Medical Economics (ESME-OC) database between 2011 and 2021. We explored progression-free survival (PFS) and overall survival (OS) benefits with PARPi maintenance. Results One hundred and twenty-three patients matching the selection criteria were included in the PARPi group and 397 patients in the control group. Median PFS was 19.9 months (95CI [15.0-21.9]) in the PARPi group vs 13.4 months (95CI [11.8-15.0]) in the control group, with a HR = 0.71 (95CI [0.55-0.93]), P = .01). Median OS was 82.0 months (95CI [48.6-Not Estimable]) in the PARPi group vs 44.7 months (95CI [38.8-53.7]) in the control group (HR = 0.47, 95CI [0.30-0.74], P < .001). Multivariate analyses including performance status, histological subtype, achievement of cytoreductive surgery at relapse, and platinum-free interval, confirmed the independent prognostic impact of PARPi treatment. Conclusion This first national study focusing on the efficacy of PARPi in a real-world population shows similar benefits than in randomized clinical trials, supporting their use in clinical routine practice. Database registration clinicaltrials.gov Identifier NCT03275298.

Tumor-intrinsic chemosensitivity assessed by KELIM and prognosis by BRCA status in patients with advanced ovarian carcinomas

Treatment of high-grade serous ovarian carcinomas relies on surgery and chemotherapy, potentially followed by bevacizumab and/or poly (ADP-ribose) polymerase inhibitors (PARPi). The modeled CA-125 ELIMination rate constant K (KELIM) is a pragmatic indicator of tumor primary chemosensitivity. Although it is well established that BRCA mutations are associated with platinum sensitivity, the relationship between BRCA status and KELIM score has yet to be elucidated. This study aimed to evaluate the interactions between BRCA and KELIM, and their respective prognostic values. We retrospectively collected data from 743 patients with high-grade serous ovarian carcinomas included in a French nationwide registry (NCT03275298) treated with neoadjuvant platinum-based chemotherapy followed by surgery. We analyzed the interactions between BRCA and KELIM, and their impacts on progression-free survival and overall survival. BRCA-mutated (BRCAm) patients had higher standardized KELIM than BRCA-wild type (BRCAwt) tumors (median 1.16 vs 1.06, respectively; p=0.001). The prognostic value of the KELIM score was independent of BRCA in multivariate analyses. KELIM score and BRCA could be combined to define three prognostic groups: (1) an unfavorable prognostic group with both BRCAwt and unfavorable KELIM (median progression-free survival 12.0months); (2) an intermediate prognostic group with either BRCAm and unfavorable KELIM, or BRCAwt and favorable KELIM (median progression-free survival of 16.0 and 18.8months, respectively; HR 0.64 compared with the unfavorable group, p<0.001); and (3) a favorable prognostic group with both BRCAm and favorable KELIM (median progression-free survival 28.8 months; HR 0.37 compared with the unfavorable group, p<0.001). The KELIM score provides complementary prognostic information with respect to BRCA, and discriminates different prognoses within BRCAm or BRCAwt patients. Patients with both BRCAwt/unfavorable KELIM have a poor prognosis, underscoring the urgent need for novel therapeutic strategies.

Shallow whole genome sequencing approach to detect Homologous Recombination Deficiency in the PAOLA-1/ENGOT-OV25 phase-III trial

AbstractThe bevacizumab (bev)/olaparib (ola) maintenance regimen was approved for BRCA1/2-mutated (BRCAmut) and Homologous Recombination Deficient (HRD) high-grade Advanced Ovarian Cancer (AOC) first line setting, based on a significantly improved progression-free survival (PFS) compared to bev alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644), where HRD was detected by MyChoice CDx PLUS test. The academic shallowHRDv2 test was developed based on shallow whole-genome sequencing as an alternative to MyChoice. Analytical and clinical validities of shallowHRDv2 as compared to MyChoice on 449 PAOLA-1 tumor samples are presented. The overall agreement between shallowHRDv2 and MyChoice was 94% (369/394). Less non-contributive tests were observed with shallowHRDv2 (15/449; 3%) than with MyChoice (51/449; 11%). Patients with HRD tumors according to shallowHRDv2 (including BRCAmut) showed a significantly prolonged PFS with bev+ola versus bev (median PFS: 65.7 versus 20.3 months, hazard ratio (HR): 0.36 [95% CI: 0.24–0.53]). This benefit was significant also for BRCA1/2 wild-type tumors (40.8 versus 19.5 months, HR: 0.45 [95% CI: 0.26–0.76]). ShallowHRDv2 is a performant, clinically validated, and cost-effective test for HRD detection.

Maintenance olaparib after platinum-based chemotherapy for advanced/metastatic endometrial cancer: GINECO randomized phase IIb UTOLA trial

Single-agent maintenance poly(ADP-ribose) polymerase (PARP) inhibition may represent an effective strategy in patients with advanced/metastatic endometrial cancer responding to platinum-based chemotherapy, including for molecular subtypes with suboptimal options. To explore this approach, we initiated the randomized phase IIb UTOLA trial (NCT03745950). Female patients without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer were randomized 2:1 to twice-daily maintenance oral olaparib 300 mg or placebo until progression or intolerance, stratified by p53 status, mismatch repair status, and response to initial chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints were PFS in subgroups, time to second progression or death, time to first and second subsequent therapy, objective response rate, overall survival, patient-reported outcomes, and safety. In the intention-to-treat population (n = 145), there was no PFS difference between olaparib and placebo (median 5.6 vs. 4.0 months, respectively; hazard ratio 0.94, 95% confidence interval 0.65-1.35; p = 0.74). However, intriguing numerical PFS effects were observed in exploratory analyses of pre-specified subgroups (p53-abnormal, complete response to initial chemotherapy, chromosomal instability). There was no overall survival difference between treatments. Grade 3/4 adverse events occurred in 36% versus 10% of olaparib- versus placebo-treated patients and were consistent with the olaparib safety profile in other cancers. Maintenance olaparib did not improve PFS, but promising numerical effects in subsets of patients warrant prospective evaluation.

Real-world dostarlimab use in advanced/recurrent endometrial cancer in France

In October 2020, the French Health Authority granted early access outside of the clinical trial setting for dostarlimab, a programmed death-1 inhibitor. Dostarlimab was approved by the European Medicines Agency (in April 2021) as monotherapy for patients with post-platinum mismatch repair deficient/microsatellite instability-high advanced/recurrent endometrial cancer, based on the results of the GARNET trial (NCT02715284). This was a real-world descriptive analysis of patients granted cohort temporary authorization of use to receive dostarlimab between November 2020 and June 2021. Physicians could complete follow-up forms at each treatment cycle to provide clinical information, safety, and efficacy data. Safety and disease progression data were also captured through pharmacovigilance reports. Of 95 temporary authorization of use requests made by 80 oncologists in 59 French hospitals, 87 patients were eligible, and 80 received≥1 dose of dostarlimab. Based on treatment response assessments received (n=43), the mean (standard deviation) time from treatment initiation to response evaluation was 11 (6) weeks. The disease control rate (complete plus partial responses plus stable disease rates) was 56% (n=24/43), and the overall response rate was 35% (n=15/43); both consistent with those reported in the GARNET trial. No new safety signals were reported. The enrolment of 80 patients in an 8-month period highlights the need for access to novel treatment regimens in France for these patients post-platinum. Prospective randomized studies are ongoing to assess the efficacy and safety of dostarlimab and other checkpoint inhibitors as first-line treatment in patients with endometrial cancer.

Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial

Endometrial cancers are characterized by frequent alterations in the PI3K-AKT-mTor, IGF1 and DNA repair signaling pathways. Concomitant inhibition of these pathways was warranted. ENDOLA phase I/II trial (NCT02755844) was designed to assess the safety/efficacy of the triplet combination of the PARP inhibitor olaparib, metronomic cyclophosphamide (50 mg daily), and PI3K-AKT-mTor inhibitor metformin (1500 mg daily) in women with recurrent endometrial carcinomas. Olaparib dose-escalation (100-300 mg twice-a-day (bid)) was used to determine the recommended-phase II-trial-dose (RP2D, primary endpoint), followed by an expansion cohort to determine the non-progression rate at 10 weeks (NPR-10w, secondary endpoint). 31 patients were treated. Olaparib RP2D was defined as 300 mg bid. The tolerability was acceptable, and grade 3-4 adverse events (51% patients) were mainly hematological. The NPR-10w was 61.5%, and the median progression-free survival (mPFS) was 5.2 months. In a post-hoc analysis, when explored by molecular subtypes/alterations, longer PFS were observed in patients with tumors characterized by a non-specific-molecular-profile (NSMP, n = 4; mPFS, 9.1 months), and by both TP53 altered & high number of large genomic alterations (LGA ≥ 8)(n = 10, mPFS, 8.6 months)). The analyses about kinetics of circulating biomarkers and pharmacodynamic effects are not reported here. In total, the benefit/toxicity ratio of the all-oral olaparib/cyclophosphamide/metformin regimen was favorable in heavily pretreated patients with recurrent endometrial cancer.

Défauts de la recombinaison homologue et inhibiteurs de PARP en thérapeutique

PARP inhibitors are effective in different types of tumors such as ovarian, breast, prostate and pancreatic cancer. Many studies are in progress and may lead to prescription evolution. PARP inhibitors prescription is almost reserved to patients with a constitutional BRCA mutation or a somatic BRCA alteration or a tumor with a deficiency in homologous recombination. Nowadays, the diagnosis of homologous recombination deficit, HRD, is possible with the prescription of a myChoice CDx (Myriad) test. PARP inhibitors are studied in association with chemotherapy and targeted therapies but also with radiotherapy and with immune checkpoint inhibitors. Access to PARP inhibitors is challenged with the emergence of resistance mechanism. Various trials are now studying the possibility of reversing these resistance mechanisms.

Prognostic nomogram for progression-free survival in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer on maintenance olaparib therapy following response to chemotherapy

The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3-11.3), 5.4 (4.8-5.8) and 2.9 (2.8-4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1-22.4) and 8.3 (7.1-10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.

Nouvelles AMMs : niraparib et olaparib en première ligne dans les cancers de l’ovaire

Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial

AbstractConcurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% [95%CI: 69.8–99.8%] with a 2-year PFS of 75% [95% CI: 56.5–99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3+ T cells to PD-L1+ tumor cells and of FOXP3+ T cells to proliferating CD11c+ myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4+ T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted.

Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201

PURPOSE This study evaluated the efficacy and safety of avutometinib (rapidly accelerated fibrosarcoma/mitogen-activated extracellular signal-regulated kinase [MEK] clamp) alone or in combination with defactinib (focal adhesion kinase inhibitor) in patients with recurrent low-grade serous ovarian cancer (LGSOC). METHODS In this phase II, open-label study, patients with recurrent, measurable LGSOC after ≥1 line of platinum chemotherapy were stratified by tumor Kirsten rat sarcoma virus homolog ( KRAS ) mutation status and randomly assigned to oral avutometinib 4.0 mg two times per week monotherapy or avutometinib 3.2 mg two times per week in combination with oral defactinib 200 mg two times per day. The combination was selected as the go-forward regimen for expansion. The primary end point was objective response rate (ORR) by blinded independent central review. RESULTS A total of 115 patients received the go-forward combination regimen. Patients had a median of 3 (range, 1-9) prior lines of therapy, including hormonal (86%), bevacizumab (51%), and MEK inhibitor (22%). Confirmed ORR was 31% (95% CI, 23% to 41%) with a median duration of response of 31.1 months (95% CI, 14.8 to 31.1). ORR was 44% in KRAS- mutant and 17% in KRAS wild-type cohorts. The median progression-free survival was 12.9 months (95% CI, 10.9 to 20.2) overall and 22.0 months (95% CI, 11.1 to 36.6) and 12.8 months (95% CI, 7.4 to 18.4) in KRAS- mutant and wild-type cohorts, respectively. The most frequent grade ≥3 treatment-related adverse events (AEs) were elevated creatine phosphokinase (24%), diarrhea (8%), and anemia (5%). Ten percent of patients discontinued because of AEs. CONCLUSION The efficacy and safety profile of avutometinib in combination with defactinib support this combination as a potential standard of care for recurrent LGSOC. A randomized phase 3 study of avutometinib and defactinib versus investigator's choice of therapy for women with recurrent LGSOC is currently enrolling (RAMP301; ClinicalTrials.gov identifier: NCT06072781 ).

Atezolizumab Combined With Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer With a Platinum-Free Interval &gt;6 Months: ENGOT-OV41/GEICO 69-O/ANITA Phase III Trial

PURPOSE To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer. METHODS The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270 ) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of &gt;6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1. RESULTS Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA- mutated, 36% PD-L1–positive, 66% TFIp &gt;12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs. CONCLUSION Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

ctDNA for Prognostication and Monitoring in Patients with Metastatic Endometrial Carcinoma Treated with Olaparib: Validation in the GINECO-UTOLA Trial

Abstract Purpose: ctDNA may offer a noninvasive means to evaluate tumor response and anticipate disease dynamics before radiologic changes in advanced endometrial carcinoma. Experimental Design: This ancillary analysis included patients from the multicenter, randomized, phase II GINECO-UTerin OLAparib (UTOLA) trial (NCT03745950) evaluating olaparib/placebo as maintenance after first-line platinum-based chemotherapy. Plasma samples were collected at screening after chemotherapy (baseline), 3 months (M3), and progression. ctDNA detection was assessed by a validated methylation-based Droplet Digital PCR (MethddPCR) assay targeting DNA positions universally methylated in endometrial carcinoma. Results: Among 130 evaluable patients, ctDNA was detected in 25 of 129 (19%, 1 technical fail) at baseline, 15 of 80 (19%) at M3, and 33 of 52 (63%) at progression. Baseline ctDNA positivity was independently associated with poorer progression-free survival (PFS) [median 1.81 vs. 7.39 months; adjusted HR = 5.33 (3.17–8.97)] and overall survival (OS) [10.3 vs. 24.7 months; adjusted HR = 3.98 (2.28–6.91); adjusted for age, stage IV at diagnosis, p53abn subgroup, and residual measurable lesions after chemotherapy]. Patients with baseline ctDNA had median OS of 9.36 months under olaparib versus 19.6 months under placebo (log-rank P = 0.05). Patients with increasing ctDNA at M3 had median PFS of 1.67 months, versus 9.64 months without, and median OS of 18.8 versus 25.8 months. ctDNA rising was predictive of poor postprogression OS under olaparib but not under placebo (interaction test, P &amp;lt; 0.001). Conclusions: MethddPCR-ctDNA is an independent prognostic biomarker for OS in advanced/metastatic endometrial carcinoma. MethddPCR-ctDNA may identify patients unlikely to benefit from PARP inhibition, guide therapeutic decisions, and should be further evaluated as a new stratification parameter in future endometrial carcinoma trials.

A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer

This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with defactinib versus Investigator's choice of treatments (ICT) in subjects with recurrent LGSOC who have progressed on a prior platinum-based therapy.

A Study of Avutometinib (VS-6766) v. Avutometinib (VS-6766) + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer With and Without a KRAS Mutation

This study will assess the safety and efficacy of avutometinib (VS-6766) monotherapy and in combination with defactinib in subjects with recurrent Low-Grade Serous Ovarian Cancer (LGSOC)

Platinum-based Chemotherapy With Atezolizumab and Niraparib in Patients With Recurrent Ovarian Cancer

Atezolizumab in this study is expected to have a positive benefit-risk profile for the treatment of patients with platinum-sensitive relapse of ovarian cancer. Of interest, atezolizumab is being investigated also in combination with platinum-based doublet chemotherapy in second line (2L)/ third line (3L) platinum-sensitive recurrent ovarian cancer patients in ATALANTE (NCT02891824), which also includes bevacizumab in the combination. The study is proceeding as expected after \>100 patients enrolled and under independent Data Monitoring Committee (IDMC) supervision. Platinum-containing therapy is considered the treatment of choice for patients with platinum-sensitive relapse. However the duration of response and the prolongation of the progression free interval with chemotherapy are usually brief, among other because these chemotherapy regimens cannot be continued until progression as they are associated with neurological, renal and hematological toxicity and cannot generally be tolerated for more than about 6 to 9 cycles. Niraparib received FDA approval in March 2017 as maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. Recently, the European Medicines Agency (EMA) has also approved niraparib as maintenance monotherapy. Despite the progress brought about by niraparib, there is a need for a more effective treatment to extend the progression free interval in this patient population. The combination with immune checkpoint inhibitors such as anti-death protein 1 (anti-PD1) or anti-death protein ligand 1 (anti-PD-L1) has a compelling rationale to this aim, especially under the light of the emerging clinical data of this combination. The use of atezolizumab concurrent to platinum-containing chemotherapy followed by niraparib as maintenance therapy after completion of chemotherapy, as per normal clinical practice, may provide further benefit to patients in terms of prolonging the progression free interval and increasing the interval between lines of chemotherapy, hence delaying further hospitalization and the cumulative toxicities associated with chemotherapy. Additionally, preliminary studies with atezolizumab suggest an acceptable tolerability profile for long term clinical use in recurrent ovarian cancer patients and other indications.

Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months (NiCOL)

To date, the majority of clinical trials on checkpoint inhibitors have tested these agents as monotherapy, and the next logical step is to evaluate rational therapeutic associations. The aim of the NiCOL study is to assess the safety of nivolumab in association with chemoradiation therapy and to gain initial insight into its efficacy in association with the current standard of care, including chemoradiation.

Evolution of the Therapeutic Care in Ovarian Cancer From 2011

The ESME Ovarian Cancer database is a multi-center real life database using a retrospective data collection process in 18 French Comprehensive Cancer Center (FCCC) over 20 sites). This database compiles data from existing data available from patient's electronic medical records (EMR).

Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Endometrial Cancer Patients

Endometrial cancer ranks 11th in terms of incidence (7275 / year) and mortality (2025 deaths/ year). The 5-year overall survivals of patients at diagnosis with locally advanced and metastatic carcinomas are about 50% and 15% respectively. Beyond first line treatment with platinum-based chemotherapy, there is lack of effective drug in this disease, which explains the poor prognosis of patients. The prognosis of metastatic endometrial cancer patients is poor, and few drugs have been shown to be effective beyond first chemotherapy line. Endometrial carcinomas are characterized by frequent alterations of PI3K-AKT-mTor; IGF1R and of DNA repair pathways. Phosphatase and tensin homologue (PTEN)-phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTor) and DNA repair pathways interact, and inhibition of PI3K-AKT-mTor signaling pathway may alter DNA damage repair. Metronomic cyclophosphamide regimen may increase the anti-proliferative effects of olaparib because it is an alkylating agent, and it exerts anti-angiogenic effects, with a favorable toxicity profile. Metformin may increase the anti-proliferative effects of olaparib because it downregulates IGF1R and PI3K-AKT-mTor pathways, with no additive toxicity.

Platine, Avastin and OLAparib in 1st Line

Randomized, Double-Blind, Phase III Trial of Olaparib vs. Placebo in Patients with Advanced FIGO Stage IIIB - IV High Grade Serous or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer treated with standard First-Line Treatment, Combining Platinum-Taxane Chemotherapy and Bevacizumab Concurrent with Chemotherapy and in Maintenance.