Margarita Romeo

Prognostic Role of Neutrophil, Monocyte and Platelet to Lymphocyte Ratios in Advanced Ovarian Cancer According to the Time of Debulking Surgery

Despite a multimodal radical treatment, mortality of advanced epithelial ovarian cancer (AEOC) remains high. Host-related factors, such as systemic inflammatory response and its interplay with the immune system, remain underexplored. We hypothesized that the prognostic impact of this response could vary between patients undergoing primary debulking surgery (PDS) and those undergoing interval debulking surgery (IDS). Therefore, we evaluated the outcomes of two surgical groups of newly diagnosed AEOC patients according to the neutrophil, monocyte and platelet to lymphocyte ratios (NLR, MLR, PLR), taking median ratio values as cutoffs. In the PDS group (n = 61), low NLR and PLR subgroups showed significantly better overall survival (not reached (NR) vs. 72.7 months, 95% confidence interval [CI]: 40.9–95.2, p = 0.019; and NR vs. 56.1 months, 95% CI: 40.9–95.2, p = 0.004, respectively) than those with high values. Similar results were observed in progression free survival. NLR and PLR-high values resulted in negative prognostic factors, adjusting for residual disease, BRCA1/2 status and stage (HR 2.48, 95% CI: 1.03–5.99, p = 0.043, and HR 2.91, 95% CI: 1.11–7.64, p = 0.03, respectively). In the IDS group (n = 85), ratios were not significant prognostic factors. We conclude that NLR and PLR may have prognostic value in the PDS setting, but none in IDS, suggesting that time of surgery can modulate the prognostic impact of baseline complete blood count (CBC).

Analysis of Tumor Microenvironment Changes after Neoadjuvant Chemotherapy with or without Bevacizumab in Advanced Ovarian Cancer (GEICO-89T/MINOVA Study)

Abstract Purpose: The aim of our study was to elucidate the impact of bevacizumab added to neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment and correlate the changes with the clinical outcome of the patients. Experimental Design: IHC and multiplex immunofluorescence for lymphoid and myeloid lineage markers were performed in matched tumor samples from 23 patients with ovarian cancer enrolled in GEICO 1205/NOVA clinical study before NACT and at the time of interval cytoreductive surgery. Results: Our results showed that the addition of bevacizumab to NACT plays a role mainly on lymphoid populations at the stromal compartment, detecting a significant decrease of CD4+ T cells, an increase of CD8+ T cells, and an upregulation in effector/regulatory cell ratio (CD8+/CD4+FOXP3+). None of the changes observed were detected in the intra-epithelial site in any arm (NACT or NACT-bevacizumab). No differences were found in myeloid lineage (macrophage-like). The percentage of Treg populations and effector/regulatory cell ratio in the stroma were the only two variables significantly associated with progression-free survival (PFS). Conclusions: The addition of bevacizumab to NACT did not have an impact on PFS in the GEICO 1205 study. However, at the cellular level, changes in CD4+, CD8+ lymphocyte populations, and CD8+/CD4+FOXP3 ratio have been detected only at the stromal site. On the basis of our results, we hypothesize about the existence of mechanisms of resistance that could prevent the trafficking of T-effector cells into the epithelial component of the tumor as a potential explanation for the lack of efficacy of ICI in the first-line treatment of advanced epithelial ovarian cancer. See related commentary by Soberanis Pina and Oza, p. 12

Atezolizumab Combined With Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer With a Platinum-Free Interval >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 >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 >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.

Bevacizumab, Atezolizumab, and Acetylsalicylic Acid in Recurrent, Platinum-Resistant Ovarian Cancer: The EORTC 1508-GCG Phase II Study

Abstract Purpose: Treatment options for patients with platinum-resistant ovarian cancer (PROC) are limited, and new therapeutic strategies are urgently needed. This phase II, randomized, multicentre trial evaluated the safety and activity of the anti–PD-L1 antibody atezolizumab (atezo) combined with the VEGF inhibitor bevacizumab (bev) and the irreversible cyclooxygenase 1/2 inhibitor aspirin [acetylsalicylic acid (ASA)] in PROC. Patients and Methods: Patients were randomized to bev monotherapy 15 mg/kg (arm 1), atezo 1,200 mg plus placebo (pbo; arm 2), atezo 1,200 mg plus ASA 320 mg/daily (arm 3), bev 15 mg/kg plus atezo 1,200 mg plus pbo (arm 4), or bev 15 mg/kg plus atezo 1,200 mg plus ASA 320 mg/daily (arm 5). Primary endpoint was progression-free survival at 6 months (PFS-6) according to RECIST v1.1 assessed by a local investigator. Secondary objectives included overall survival, PFS, second PFS (PFS2), and tolerability. Time to first subsequent therapy (TFST) was evaluated in a post hoc analysis. Results: In arms 1 (bev), 4 (bev–atezo–pbo), and 5 (bev–atezo–ASA), there were 7/32 [21.9%, 70% confidence interval (CI), 14.0–32.0], 8/32 (25.0%, 70% CI, 16.6–35.3), and 8/32 (25.0%, 70% CI, 16.6–35.3) patients alive and progression-free at 6 months. The primary objective was not reached in any arm. Median PFS and response rates were 2.3 for bev monotherapy, 4.1 for bev–atezo–pbo, and 4.0 months for bev–atezo–ASA and 10%, 19%, and 15%, respectively. Two patients achieved an ongoing complete response lasting for more than 5 years from randomization (1 in bev–atezo–pbo and 1 in bev–atezo–ASA). A post hoc analysis of TFST suggested benefit of adding bev to atezo–ASA (P < 0.001). Tumor-infiltrating lymphocytes (TIL) increased in the atezo-containing arms after the first two cycles, and increased TIL were associated with a significantly longer TFST. Conclusions: The addition of ASA to bev plus atezo was well-tolerated but did not improve efficacy in PROC. Relative to bev alone, the bev plus atezo combination numerically improved PFS. Exploratory translational analyses suggest clinical benefit in a subgroup of patients characterized by high TIL infiltration and PD-L1–positive tumors at baseline.

Addressing unmet needs in long-term survivors of ovarian cancer (ENGOT ov40/NOGGO S13/GEICO 71-R/Expression VI): insights from a Spanish cohort

Ovarian cancer remains a significant global health concern. Contemporary therapeutics have led to an increased number of long-term survivors. This research investigates the unmet needs of long-term ovarian cancer survivors in Spain, focusing on persistent side effects, patient concerns, lifestyle changes, and ongoing challenges. This is a multi-center, cross-sectional, observational study, assessing the results from the international North-Eastern German Society of Gynecological Oncology survey, Expression VI - Long-term survival with ovarian cancer in Spain. Participants were identified during follow-up visits at oncology departments. A structured questionnaire of 68 items, including demographic, clinical, psychosocial, and lifestyle domains, was completed anonymously in printed format, with implied consent through survey completion. A total of 250 long-term ovarian cancer survivors from Spain, defined as patients diagnosed of malignant ovarian cancer with a survival ≥8 years since diagnosis (median age at diagnosis 52 years; median survival time 11 years), completed the survey. A substantial number of participants continued to experience long-term side effects, including gastrointestinal (90%), dermatologic (91.6%), and neurologic symptoms, such as memory problems (15.1%) and concentration difficulties (10.8%). Nearly half of the survivors (47.3%) expressed concerns about nervousness, 43.6% reported ongoing pain, and 40% struggled with sleep disturbances. Lifestyle changes after cancer diagnostic were significant, with 56.5% of smoker participants quitting or reducing smoking and 41.6% adopting healthier diets. Finally, our results indicate that most participants received some form of follow-up, primarily through blood biomarker monitoring (87.0%) and imaging tests (73.0%). This study highlights the persistent challenges among long-term ovarian cancer survivors in Spain, stressing the need for more comprehensive, tailored aftercare. These findings may be generalized to other regions, emphasizing the importance of addressing ongoing side effects and unmet care needs to improve survivors' long-term quality of life. Enhanced follow-up care, patient support, and effective communication are essential components of this effort.

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.