Eric Pujade Lauraine

Early Clinical and Molecular Biomarkers in Patients With Advanced Ovarian Cancer Undergoing Neoadjuvant Chemotherapy: CHIVA Phase II GINECO Trial

PURPOSE Platinum-based chemotherapy and surgery are pivotal in managing ovarian cancer (OC), yet prognosis remains poor, and early biomarkers for platinum resistance are needed. The neoadjuvant setting provides an opportunity to evaluate tumor responsiveness to platinum chemotherapy in vivo. This study evaluated whether early measures of platinum response combined with molecular alterations could predict surgical outcomes and survival in patients with OC treated with neoadjuvant chemotherapy (NACT). METHODS The CHIVA study enrolled stage III/IV OC patients eligible for three cycles NACT with or without nintedanib, followed by interval debulking surgery. Archival samples underwent extensive sequencing to detect clinically relevant variants and copy number alterations and calculate genomic instability (GIS). Early chemotherapy response measures—cancer antigen 125 kinetics by KELIM, major pathologic response, GIS status, tumor infiltrating lymphocytes (TILs) abundance, and genomic alterations—were correlated with surgery completeness and survival. RESULTS Among 127 patients, the overall response rate was 44%, and the complete cytoreduction (CC0) rate was 54.8%. Homologous recombination deficiency (HRD) was identified in 56% of patients and was associated with better survival. The median progression-free survival was 21.4, 20.5, and 14.4 months in the BRCAmut , BRCAwt /GIS-high, and BRCAwt /GIS-low subgroups, respectively ( P = .001). Unfavorable KELIM predicted lower objective response rate, CC0, and shorter survival, while low intraepithelial TILs (ieTILs) correlated with poor outcomes. Multivariate analysis confirmed KELIM, HRD status, and ieTILs as independent biomarkers. CCNE1 amplifications, observed in 20% of patients, were associated with moderate chemotherapy sensitivity. CONCLUSION HRD status, KELIM, and TILs are key independent biomarkers in advanced OC. CCNE1 amplifications, although typically associated with platinum resistance, were linked to moderate chemotherapy sensitivity, defining an intermediate prognostic subgroup.

Geneva Homologous Recombination Deficiency Test Is Predictive of Survival Benefit From Olaparib and Bevacizumab Maintenance in Ovarian Cancer

PURPOSE The ability of the Geneva homologous recombination deficiency (HRD) test to predict progression-free survival (PFS) in patients with high-grade ovarian cancer treated with poly (ADP-ribose) polymerase inhibitors has been demonstrated. Its performance with respect to overall survival (OS) has not been assessed yet. METHODS Using the final results of the PAOLA-1/ENGOT-ov25 phase III clinical trial with a median follow-up of 5 years, we evaluated the Geneva HRD test on 468 samples as part of the ENGOT HRD European Initiative. Results were evaluated in terms of final PFS and OS in the olaparib + bevacizumab and placebo + bevacizumab arms and compared with the Myriad MyChoice HRD test. RESULTS Final PFS was consistent with previously published data and confirmed the predictive value of the Geneva HRD test with a hazard ratio (HR) of 0.41 (95% CI, 0.30 to 0.57) for HRD-positive patients. The results for OS showed a HR of 0.56 (95% CI, 0.37 to 0.85) for HRD-positive patients and 1.6 (95% CI, 1.1 to 2.3) for HRD-negative patients. These results are consistent with those observed with the Myriad test, including the negative OS trend in the HRD-negative subgroup treated with olaparib + bevacizumab (HR, 1.2 [95% CI, 0.83 to 1.8]). A subgroup analysis of patients with intermediate HRD scores showed that the normalized large-scale state transition score used by the Geneva HRD test had both predictive and prognostic value. CONCLUSION The Geneva HRD test predicts PFS and OS benefit from olaparib + bevacizumab. The potential detrimental effect of olaparib + bevacizumab on OS in the HRD-negative population is hypothesis-generating and needs to be confirmed prospectively.

GANNET53 Part II: A European Phase I/II Trial of the HSP90 Inhibitor Ganetespib in High-Grade Platinum-Resistant Ovarian Cancer—A Study of the GANNET53 Consortium

Abstract Purpose: Mutant p53 stabilized by heat shock protein 90 (HSP90) is a novel target in oncology. The open-label, randomized phase II GANNET53 trial is the first to evaluate the HSP90 inhibitor ganetespib (G) with paclitaxel (P) in platinum-resistant epithelial ovarian cancer (EUDRACT 2013-003868-31; EU FP7 #602602). Patients and Methods: Patients were randomized 2:1 to receive G + P or P alone until progression. Primary endpoints were progression-free survival (PFS) and PFS rate at 6 months. Exploratory endpoints were biomarkers based on p53 and HSP90. Results: A total of 133 patients were enrolled. The median PFS was 3.5 (G + P) and 5.3 months (P) (HR = 1.3; 95% confidence interval, 0.897–1.895; P = 0.16), and PFS rates at 6 months were 22% (G + P) and 33% (P). No significant differences were found in overall survival, objective response rate, and post-progression PFS between arms. The most frequent adverse events were diarrhea (79% vs. 26%), anemia (46% vs. 51%), nausea (41% vs. 40%), and peripheral neuropathy (36% vs. 47%). Serious adverse events were more common in G + P (39.5% vs. 23.3%). Gastrointestinal perforation was a new safety finding. Despite a high TP53 mutation frequency, HSP90–p53 complexes were detected in only 39.6% of the cases and were also detected stably during treatment. In vitro, no synergistic effects of G + P were observed, and mutant p53 depletion did not sensitize ovarian cancer cells to treatment. Conclusions: Although no major safety findings were observed, G + P did not lead to survival benefit. Our companion diagnostic program confirmed that G + P do not favorably cooperate in killing ovarian cancer cells.

Poor Concordance Between Cancer Antigen-125 and RECIST Assessment for Progression in Patients With Platinum-Sensitive Relapsed Ovarian Cancer on Maintenance Therapy With a Poly(ADP-ribose) Polymerase Inhibitor

PURPOSE Cancer antigen-125 (CA-125) is recommended by treatment guidelines and widely used to diagnose ovarian cancer recurrence. The value of CA-125 as a surrogate for disease progression (PD) and its concordance with radiologic progression are unclear, particularly for women with platinum-sensitive relapsed ovarian cancer (PSROC) who have responded to chemotherapy and treated with maintenance poly(ADP-ribose) polymerase inhibitor (PARPi). METHODS In this pooled analysis of four randomized trials of maintenance PARPi or placebo (Study 19, SOLO2, ARIEL3, and NOVA), we extracted data on CA-125 PD as defined by Gynecologic Cancer InterGroup criteria and RECIST v1.1. We evaluated the concordance between CA-125 and RECIST PD and reported on the negative predictive value (NPV) and positive predictive value (PPV). RESULTS Of 1,262 participants (n = 818 PARPi, n = 444 placebo), 403 (32%) had CA-125 PD, and of these, 366 had concordant RECIST PD (PPV, 91% [95% CI, 88 to 93]). However, of 859 (68%) without CA-125 PD, 382 also did not have RECIST PD (NPV, 44% [95% CI, 41 to 48]). Within the treatment arms, PPV remained high (PARPi, 91% [95% CI, 86 to 94]; placebo, 91% [95% CI, 86 to 95]) but NPV was lower on placebo (PARPi, 53% [95% CI, 49 to 57]; placebo, 25% [95% CI, 20 to 31]). Of 477 with RECIST-only PD, most (95%) had a normal CA-125 at the start of maintenance therapy and the majority (n = 304, 64%) had CA-125 that remained within normal range. Solid organ recurrence without peritoneal disease was more common in those with RECIST-only PD than in those with CA-125 and RECIST PD (36% v 24%; P < .001). CONCLUSION In patients with PSROC treated with maintenance PARPi, almost half with RECIST PD did not have CA-125 PD, challenging current guidelines. Periodic computed tomography imaging should be considered as part of surveillance, particularly in those with a normal CA-125 at the start of maintenance therapy and on treatment.

Normalized LST Is an Efficient Biomarker for Homologous Recombination Deficiency and Olaparib Response in Ovarian Carcinoma

PURPOSE The efficiency of the Myriad Homologous Recombination Deficiency (HRD) test to guide the use of poly (ADP-ribose) polymerase (PARP) inhibitors has been demonstrated in several phase III trials. However, a need exists for alternative clinically validated tests. METHODS A novel biomarker for HRD was developed using The Cancer Genome Atlas database and, as part of the ENGOT HRD European Initiative, applied to 469 samples from the PAOLA-1/ENGOT-ov25 trial. Results were compared with the Myriad myChoice Genomic Instability Score (GIS) with respect to the progression-free survival in the olaparib + bevacizumab and placebo + bevacizumab arms. RESULTS Analysis of the TCGA cohort revealed that a normalization of the number of large-scale state transitions by the number of whole-genome doubling events allows a better separation and classification of HRD samples than the GIS. Analysis of the PAOLA-1 samples, using the Geneva test (OncoScan + nLST), yielded a lower failure rate (27 of 469 v 59 of 469) and a hazard ratio of 0.40 (95% CI, 0.28 to 0.57) compared with 0.37 for Myriad myChoice (BRCAm or GIS+) in the nLST-positive samples. In patients with BRCAwt, the Geneva test identified a novel subpopulation of patients, with a favorable 1-year PFS (85%) but a poor 2-year PFS (30%) on olaparib + bevacizumab treatment. CONCLUSION The proposed test efficiently separates HRD-positive from HRD-negative patients, predicts response to PARP inhibition, and can be easily deployed in a clinical laboratory for routine practice. The performance is similar to the available commercial test, but its lower failure rate allows an increase in the number of patients who will receive a conclusive laboratory result.

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.

Predicting benefit from PARP inhibitors using deep learning on H&E-stained ovarian cancer slides

Ovarian cancer patients with a Homologous Recombination Deficiency (HRD) often benefit from polyadenosine diphosphate-ribose polymerase (PARP) inhibitor maintenance therapy after response to platinum-based chemotherapy. HR status is currently analyzed via complex molecular tests. Predicting benefit from PARP inhibitors directly on histological whole slide images (WSIs) could be a fast and cheap alternative. We trained a Deep Learning (DL) model on H&E stained WSIs with "shrunken centroid" (SC) based HRD ground truth using the AGO-TR1 cohort (n = 208: 108 training, 100 test) and tested its ability to predict HRD as evaluated by the Myriad classifier and the benefit from olaparib in the PAOLA-1 cohort (n = 447) in a blinded manner. In contrast to the HRD prediction AUROC of 72 % on hold-out, our model only yielded an AUROC of 57 % external. Kaplan-Meier analysis showed that progression free survival (PFS) in the PARP inhibitor treated PAOLA-1 patients was significantly improved in the HRD positive group as defined by our model, but not in the HRD negative group. PFS improvement in PARP inhibitor-treated patients was substantially longer in our HRD positive group, hinting at a biologically meaningful prediction of benefit from PARP inhibitors. Together, our results indicate that it might be possible to generate a predictor of benefit from PARP inhibitors based on the DL-mediated analysis of WSIs. However, further studies with larger cohorts and further methodological improvements will be necessary to generate a predictor with clinically useful accuracy across independent patient cohorts.

Spatial Profiling of Ovarian Carcinoma and Tumor Microenvironment Evolution under Neoadjuvant Chemotherapy

Abstract Purpose: This study investigates changes in CD8+ cells, CD8+/Foxp3 ratio, HLA I expression, and immune coregulator density at diagnosis and upon neoadjuvant chemotherapy (NACT), correlating changes with clinical outcomes. Experimental Design: Multiplexed immune profiling and cell clustering analysis were performed on paired matched ovarian cancer samples to characterize the immune tumor microenvironment (iTME) at diagnosis and under NACT in patients enrolled in the CHIVA trial (NCT01583322). Results: Several immune cell (IC) subsets and immune coregulators were quantified pre/post-NACT. At diagnosis, patients with higher CD8+ T cells and HLA I+-enriched tumors were associated with a better outcome. The CD8+/Foxp3+ ratio increased significantly post-NACT in favor of increased immune surveillance, and the influx of CD8+ T cells predicted better outcomes. Clustering analysis stratified pre-NACT tumors into four subsets: high Binf, enriched in B clusters; high Tinf and low Tinf, according to their CD8+ density; and desert clusters. At baseline, these clusters were not correlated with patient outcomes. Under NACT, tumors were segregated into three clusters: high BinfTinf, low Tinf, and desert. The high BinfTinf, more diverse in IC composition encompassing T, B, and NK cells, correlated with improved survival. PDL1 was rarely expressed, whereas TIM3, LAG3, and IDO1 were more prevalent. Conclusions: Several iTMEs exist during tumor evolution, and the NACT impact on iTME is heterogeneous. Clustering analysis of patients unravels several IC subsets within ovarian cancer and can guide future personalized approaches. Targeting different checkpoints such as TIM3, LAG3, and IDO1, more prevalent than PDL1, could more effectively harness antitumor immunity in this anti-PDL1–resistant malignancy.

Validation of the Clinical Use of GIScar, an Academic-developed Genomic Instability Score Predicting Sensitivity to Maintenance Olaparib for Ovarian Cancer

Abstract Purpose: The optimal application of maintenance PARP inhibitor therapy for ovarian cancer requires accessible, robust, and rapid testing of homologous recombination deficiency (HRD). However, in many countries, access to HRD testing is problematic and the failure rate is high. We developed an academic HRD test to support treatment decision-making. Experimental Design: Genomic Instability Scar (GIScar) was developed through targeted sequencing of a 127-gene panel to determine HRD status. GIScar was trained from a noninterventional study with 250 prospectively collected ovarian tumor samples. GIScar was validated on 469 DNA tumor samples from the PAOLA-1 trial evaluating maintenance olaparib for newly diagnosed ovarian cancer, and its predictive value was compared with Myriad Genetics MyChoice (MGMC). Results: GIScar showed significant correlation with MGMC HRD classification (kappa statistics: 0.780). From PAOLA-1 samples, more HRD-positive tumors were identified by GIScar (258) than MGMC (242), with a lower proportion of inconclusive results (1% vs. 9%, respectively). The HRs for progression-free survival (PFS) with olaparib versus placebo were 0.45 [95% confidence interval (CI), 0.33–0.62] in GIScar-identified HRD-positive BRCA-mutated tumors, 0.50 (95% CI, 0.31–0.80) in HRD-positive BRCA-wild-type tumors, and 1.02 (95% CI, 0.74–1.40) in HRD-negative tumors. Tumors identified as HRD positive by GIScar but HRD negative by MGMC had better PFS with olaparib (HR, 0.23; 95% CI, 0.07–0.72). Conclusions: GIScar is a valuable diagnostic tool, reliably detecting HRD and predicting sensitivity to olaparib for ovarian cancer. GIScar showed high analytic concordance with MGMC test and fewer inconclusive results. GIScar is easily implemented into diagnostic laboratories with a rapid turnaround.