Health-related quality of life in patients with newly diagnosed advanced ovarian cancer treated with niraparib vs placebo: Results from the phase 3 randomized PRIMA/ENGOT-OV26/GOG-3012 trial.

OBJECTIVE: To assess patient-reported health-related quality of life (HRQoL) in patients with ovarian cancer (OC) who received niraparib as first-line maintenance therapy. METHODS: PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) enrolled patients with newly diagnosed advanced OC who responded to first-line platinum-based chemotherapy. Patients were randomized (2:1) to niraparib or placebo once daily in 28-day cycles until disease progression, intolerable toxicity, or death. HRQoL was assessed as a prespecified secondary end point using patient-reported responses to the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30), the EORTC QLQ Ovarian Cancer Module (EORTC QLQ-OV28), the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), and EQ-5D-5L questionnaires. Assessments were collected at baseline and every 8 weeks (±7 days) for 56 weeks, beginning on cycle 1/day 1, then every 12 weeks (±7 days) thereafter while the patient received study treatment. RESULTS: Among trial participants (niraparib, n = 487; placebo, n = 246), PRO adherence exceeded 80% for all instruments across all cycles. Patients reported no decline over time in HRQoL measured via EORTC QLQ-C30 Global Health Status/QoL and FOSI overall scores. Scores for abdominal/gastrointestinal symptoms (EORTC QLQ-OV28) and nausea and vomiting, appetite loss, and constipation (EORTC QLQ-C30) were higher (worse symptoms) in niraparib-treated patients than placebo-treated patients; except for constipation, these differences resolved over time. Patients did not self-report any worsening from baseline of fatigue, headache, insomnia, or abdominal pain on questionnaires. CONCLUSIONS: Despite some early, largely transient increases in gastrointestinal symptoms, patients with OC treated with niraparib first-line maintenance therapy reported no worsening in overall HRQoL.

Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer.

PURPOSE: Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53 and has clinical activity in endometrial cancer (EC). The primary end point was to assess progression-free survival (PFS) with once-weekly oral selinexor in patients with advanced or recurrent EC. PATIENTS AND METHODS: ENGOT-EN5/GOG-3055/SIENDO was a randomized, prospective, multicenter, double-blind, placebo-controlled, phase III study at 107 sites in 10 countries. Patients 18 years or older with histologically confirmed EC were enrolled. All had completed a single line of at least 12 weeks of taxane-platinum combination chemotherapy and achieved partial or complete response. Patients were assigned to receive 80 mg oral selinexor once weekly or placebo with 2:1 random assignment (ClinicalTrials.gov identifier: NCT03555422). RESULTS: Between January 2018 and December 2021, 263 patients were randomly assigned, with 174 allocated to selinexor and 89 to placebo. The median PFS was 5.7 months (95% CI, 3.81 to 9.20) with selinexor versus 3.8 months (95% CI, 3.68 to 7.39) with placebo (hazard ratio [HR], 0.76 [95% CI, 0.54 to 1.08]; two-sided P = .126), which did not meet the criteria for statistical significance in the intent-to-treat population. Incorrect chemotherapy response stratification data for 7 (2.7%) patients were identified. In a prespecified exploratory analysis of PFS in audited stratification data, PFS for selinexor met the threshold for statistical significance (HR, 0.71; 95% CI, 0.499 to 0.996; two-sided P = .049). Furthermore, patients with the TP53 wild-type (wt) EC had a median PFS of 13.7 and 3.7 months with selinexor and placebo. The most common grade 3 treatment-related adverse events were nausea (9%), neutropenia (9%), and thrombocytopenia (7%). CONCLUSION: The significance level for PFS was only met in the audited analysis. However, a preliminary analysis of a prespecified exploratory subgroup of patients with TP53wt EC showed promising results with selinexor maintenance therapy.

The Prognostic Significance of Tumor-Infiltrating Lymphocytes, PD-L1, BRCA Mutation Status and Tumor Mutational Burden in Early-Stage High-Grade Serous Ovarian Carcinoma-A Study by the Spanish Group for Ovarian Cancer Research (GEICO).

Early stages are under-represented in studies on the molecular and immune features of high-grade serous ovarian carcinoma (HGSOC), and specific studies focused on early-stage HGSOC are required for a better prognostic stratification and to personalize chemotherapy. The aim of this study was to determine the prognostic significance of CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs), tumoral cell PD-L1 expression, BRCA mutational status and tumor mutation burden (TMB) in early-stage HGSOC. A retrospective study was performed on stage I and II HGSOC from the Molecular Reclassification of Early Stages of Ovarian Cancer (RECLAMO) cohort from the Spanish Group of Ovarian Cancer Research (GEICO). Centralized histological typing was performed based on morphological and immunohistochemical features. Intraepithelial (i) and stromal (s) CD8+ and CD4+ T cells and PD-L1 were evaluated on tissue microarrays by immunohistochemistry. BRCA1 and BRCA2 mutation status and TMB were analyzed in tumor DNA using next-generation sequencing. The study included 124 tumors. High iCD8+ (>20 TILs/core), low/intermediate CD4+ (<20 TILs/core) and high CD8+/CD4+ ratio (>35/core) were associated with favorable outcomes. Tumor cell PD-L1 expression (TPS ≥ 1) was present in only 8% of tumors. In total, 11 (16%) and 6 (9%) out of 69 HGSOC tested carried pathogenic or likely pathogenic BRCA1 or BRCA2 mutations, respectively. Median TMB of 40 tumors analyzed was 5.04 mutations/Mb and only 6 tumors had 10 or more mutations/Mb. BRCA status and TMB were not associated with TILs or prognosis. When compared with studies on advanced HGSOC, our results suggested that prognostic variables differed according to stage and that more studies focused on early stages of HGSOC are needed to better stratify these tumors.

Maintained complete response to talazoparib in a BRCA-2 mutated metastatic luminal breast cancer: case report and review of literature.

PARP inhibitors are progressively becoming a part of our therapeutic arsenal against BRCA-defective tumors, because of their capacity to induce synthetic lethality in cells with a deficiency in the homologous recombination repair system. Olaparib and talazoparib have been approved for metastatic breast cancer in carriers of germline BRCA mutations, which are found in approximately 6% of patients with breast cancer. We report the case of a patient with metastatic breast cancer, carrier of a germline mutation in BRCA2, with a complete response to first-line treatment with talazoparib, maintained after 6 years. To the best of our knowledge, this is the longest response reported with a PARP inhibitor in a BRCA-mutated tumor. We have made a review of literature, regarding the rationale for PARP inhibitors in carriers of BRCA mutations and their clinical relevance in the management of advanced breast cancer, as well as their emerging role in early stage disease, alone and in combination with other systemic therapies.

Prospective evaluation of the tolerability and efficacy of niraparib dosing based on baseline body weight and platelet count: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

BACKGROUND: The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose. RESULTS: Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46-0.76] vs. ISD HR, 0.69 [95% CI, 0.48-0.98]) and the homologous recombination-deficient (FSD HR, 0.44 [95% CI, 0.30-0.64] vs. ISD HR, 0.39 [95% CI, 0.22-0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD. CONCLUSIONS: In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.

Discordant Humoral and T-Cell Response to mRNA SARS-CoV-2 Vaccine and the Risk of Breakthrough Infections in Women with Breast Cancer, Receiving Cyclin-Dependent Kinase 4 and 6 Inhibitors.

Few data are available about the immune response to mRNA SARS-CoV-2 vaccines in patients with breast cancer receiving cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). We conducted a prospective, single-center study of patients with breast cancer treated with CDK4/6i who received mRNA-1273 vaccination, as well as a comparative group of healthcare workers. The primary endpoint was to compare the rate and magnitude of humoral and T-cell response after full vaccination. A better neutralizing antibody and anti-S IgG level was observed after vaccination in the subgroup of women receiving CDK4/6i, but a trend toward a reduced CD4 and CD8 T-cell response in the CDK4/6i group was not statistically significant. There were no differences in the rate of COVID-19 after vaccination (19% vs. 12%), but breakthrough infections were observed in those with lower levels of anti-S IgG and neutralizing antibodies after the first dose. A lower rate of CD4 T-cell response was also found in those individuals with breakthrough infections, although a non-significant and similar level of CD8 T-cell response was also observed, regardless of breakthrough infections. The rate of adverse events was higher in patients treated with CDK4/6i, without serious adverse events. In conclusion, there was a robust humoral response, but a blunted T-cell response to mRNA vaccine in women receiving CDK4/6i, suggesting a reduced trend of the adaptative immune response.

Clinical and molecular signature of survival and resistance to olaparib plus pegylated liposomal doxorubicin in platinum-resistant ovarian cancer: a stratified analysis from the phase II clinical trial ROLANDO, GEICO-1601.

OBJECTIVE: To determine the potential prognostic value of clinical and molecular biomarkers in the survival of patients with platinum-resistant ovarian cancer treated with olaparib and pegylated liposomal doxorubicin. METHODS: ROLANDO was a single-arm phase II trial that included patients with high-grade serous or endometrioid tumors and at least one previous platinum-resistant recurrence regardless of BRCA status. Patients received 6 cycles of pegylated liposomal doxorubicin every 28 days plus olaparib 300 mg twice daily. followed by olaparib 300 mg twice daily; monotherapy until progression or unacceptable toxicity. Prognostic factors including previous lines (and platinum-containing ones), BRCA mutation status, previous bevacizumab, CA-125 levels, and the neutrophil/lymphocyte ratio, lymphocyte/monocyte ratio, and platelet/lymphocyte ratio calculated at inclusion were analyzed through a multivariate logistic regression and factor analysis of mixed data. RESULTS: Thirty-one patients were included. Median age was 57 years (range 43-75), Eastern Cooperative Oncolgy Group performance status 0/1: 32.3%/67.7% and BRCA mutated: 16.1%. Prior treatment lines were >2 lines: 14 (45.2%) patients, ≥2 platinum lines: 21 patients (67.7%) and previous bevacizumab 19 (61.3%) patients. CA-125 was >2 upper limit normal in 24 (77.4%) patients. A high neutrophil/lymphocyte ratio was associated with worse overall survival by univariate/multivariate regression model (HR=11.18; 95% CI 1.1 to 114.5; p=0.042). No other factors were associated with overall survival in the multivariate model. A multifactorial signature based on clinical and molecular baseline characteristics was capable of defining six patient clusters. Three of these clusters had significantly better prognosis, with a median overall survival of 21.3 months (95% CI 12.2 to not reached). CONCLUSIONS: High neutrophil/lymphocyte ratio at platinum-resistant relapse indicated poor prognosis in patients treated with olaparib plus pegylated liposomal doxorubicin. A multifactorial clinical signature was more precise than single variables for implying the prognosis and may help in therapeutic assignment after further validation in large prospective cohorts.

Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03.

BACKGROUND: Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole. METHODS: We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings. RESULTS: From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors" (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43-22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99-36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies. CONCLUSION: Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857). GOV IDENTIFIER: NCT01584297.

Real-world safety and effectiveness of maintenance niraparib for platinum-sensitive recurrent ovarian cancer: A GEICO retrospective observational study within the Spanish expanded-access programme.

AIM: To describe patient characteristics, effectiveness and safety in a real-world population treated with niraparib in the Spanish expanded-access programme. PATIENTS AND METHODS: This retrospective observational study included women with platinum-sensitive recurrent high-grade serous ovarian cancer who received maintenance niraparib within the Spanish niraparib expanded-access programme. Eligible patients had received ≥2 previous lines of platinum-containing therapy, remained platinum-sensitive after the penultimate line of platinum and had responded to the most recent platinum-containing therapy. Niraparib dosing was at the treating physician's discretion (300 mg/day fixed starting dose or individualised starting dose [ISD] according to baseline body weight and platelet count). Safety, impact of dose adjustments, patient characteristics and effectiveness were analysed using data extracted from medical records. RESULTS: Among 316 eligible patients, 80% had BRCA wild-type tumours and 66% received an ISD. Median niraparib duration was 7.8 months. The most common adverse events typically occurred within 3 months of starting niraparib. Median progression-free survival was 8.6 (95% confidence interval [CI] 7.6-10.0) months. One- and 2-year overall survival rates were 86% (95% CI 81-89%) and 65% (95% CI 59-70%), respectively. Dose interruptions, dose reductions, haematological toxicities and asthenia/fatigue were less common with ISD than fixed starting dose niraparib, but progression-free survival was similar irrespective of dosing strategy. Subsequent therapy included platinum in 71% of patients who received further treatment. CONCLUSION: Outcomes in this large real-world dataset of niraparib-treated patients are consistent with phase III trials, providing reassuring evidence of the tolerability and activity of niraparib maintenance therapy for platinum-sensitive recurrent ovarian cancer. GOV REGISTRATION: NCT04546373.

Safety of bevacizumab and olaparib as frontline maintenance therapy in advanced ovarian cancer: expert review for clinical practice.

Olaparib, a poly(ADP-ribose) polymerase inhibitor, in combination with the antiangiogenic agent bevacizumab, is approved as maintenance therapy for patients with newly diagnosed stage III or IV epithelial ovarian cancer who have homologous recombination deficient tumors with a deleterious or suspected deleterious BRCA mutation and/or genomic instability based on the long-lasting survival benefit observed in the PAOLA-1 trial. Despite treatment with olaparib and bevacizumab showing an acceptable safety profile, the rate of discontinuations due to adverse events was relatively high, and toxicity related to this regimen may restrict its clinical use. Proper management of olaparib/bevacizumab-related adverse events is important for the improvement of quality of life and maximization of the efficacy of maintenance therapy. Here, we summarize the safety results of the PAOLA-1 study, focusing on treatment discontinuation reasons and adverse event profiles. We sought to shed light on toxicity monitoring and prevention, providing concise recommendations for the clinical management of the most relevant side effects.

Morphological Diversity of Calretinin Interneurons Generated From Adult Mouse Olfactory Bulb Core Neural Stem Cells.

Neural stem cells (NSCs) in the olfactory bulb (OB) core can generate mature interneurons in the adult mice brain. The vast majority of these adult generated cells express the calcium-binding protein Calretinin (CalR), and they migrate towards different OB layers. However, these cells have yet to be fully characterized and hence, to achieve this we injected retroviral particles expressing GFP into the OB core of adult animals and found that the CalR+ neurons generated from NSCs mainly migrate to the granule cell layer (GCL) and glomerular layer (GL) in similar proportions. In addition, since morphology and function are closely related, we used three-dimensional imaging techniques to analyze the morphology of these adult born cells, describing new subtypes of CalR+ interneurons based on their dendritic arborizations and projections, as well as their localization in the GCL or GL. We also show that the migration and morphology of these newly generated neurons can be altered by misexpressing the transcription factor Tbr1 in the OB core. Therefore, the morphology acquired by neurons located in a specific OB layer is the result of a combination of both extrinsic (e.g., layer allocation) and intrinsic mechanisms (e.g., transcription factors). Defining the cellular processes and molecular mechanisms that govern adult neurogenesis might help better understand brain circuit formation and plasticity, as well as eventually opening the way to develop strategies for brain repair.

Defining a Standard Set of Patient-Reported Outcomes for Patients With Advanced Ovarian Cancer.

Purpose: Advanced ovarian cancer (AOC) and its treatment cause several symptoms and impact on patients' health-related quality of life (HRQoL). We aim to reach a consensus on the most relevant patient-reported outcome (PROs), the corresponding measures (PROMs), and measurement frequency during AOC patients' follow-up from patients' and healthcare professionals' (HCP) perspective. Methods: The project comprised five steps: 1) a literature review, 2) a focus group with patients, 3) a nominal group with HCP, 4) two round-Delphi consultations with patients and HCP, and 5) a final meeting with HCP. Delphi questionnaire was elaborated based on literature review, focus group (n=5 patients), and nominal group (n=16 HCP). The relevance of each PRO and the appropriateness (A) and feasibility (F) of the proposed PROM were assessed (Likert scale 1=strongly agree; 9=strongly disagree). The consensus was reached when at least 75% of the panelists rated it as 'relevant', 'appropriate', or 'feasible' (score 7-9). Results: A total of 56 HCP [51.8% Hospital Pharmacy; 41.1% Oncology; 3.6% Nursing; and 3.6% Psycho-oncology; mean time in specialty 12.5 (8.0) years] and 10 AOC patients [mean time diagnosis 5.4 (3.0) years] participated in the 1st round. All PROs achieved consensus regarding their relevance, except dry skin (58.0%). Agreement was reached for PRO-CTCAE to be used to assess fatigue (A:84.9%; F:75.8%), neuropathy (A:92.4%; F:77.3%), diarrhea (A:87.9%; F:88.7%), constipation (A:86.4%; F:75.8%), nausea (A:89.4%; F:75.8%), insomnia (A:81.8%; F:88.7%), abdominal bloating (A:82.2%; F:82.2%) and sexuality (A:78.8%; F:88.6%); EQ-5D to determine patients' HRQoL (A:87.9%; F:80.3%), pain (A:87.9%; F:75.8%) and mood (A:77.7%; F:85.5%); to assess treatment adherence the Morisky-Green (A:90.9%; F:84.9%) and the dispensing register (A:80.3%; F:80.3%) were chosen. It was agreed to note in the medical record whether the patient's treatment preferences had been considered during decision-making (A:78.8%; F:78.8%) and to use a 5-point Likert scale to assess treatment satisfaction (A:86.4%; F:86.4%). Panelists agreed (A:92.4%; F: 77.3%) to collect these PROs (1) at the time of diagnosis/relapse; (2) one month after starting treatment/change therapeutic strategy; (3) every three months during the 1st-year of treatment; and later (4) every six months until treatment completion/change. Conclusions: The consensus reached represents the first step towards including the patient's perspective in AOC follow-up. The standardized collection of PROs in clinical practice may contribute to optimizing the follow-up of these patients and thus improving the quality of care.

Prospective Real-World Gynaecological Cancer Clinical Registry with Associated Biospecimens: A Collaborative Model to Promote Translational Research between GEICO and the Spanish Biobank Network.

Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer.

Phase 2 Trial (POLA Study) of Lurbinectedin plus Olaparib in Patients with Advanced Solid Tumors: Results of Efficacy, Tolerability, and the Translational Study.

We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1-5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. Results: A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0-5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinical benefit was observed for cases with HRR gene mutation. In ovarian LTRs, although a direct association with GI and a total loss of heterozygosity (LOH) events was observed, the association did not reach statistical significance (p = 0.055). Globally, the total number of LOHs might be associated with the ORR (p =0.074). The most common grade 3-4 toxicities were anemia and thrombocytopenia, in 6 (8.2%) and 3 (4.1%) patients, respectively. Conclusion: The POLA study provides evidence that the administration of lurbinectedin and olaparib is feasible and tolerable, with a DCR of 72.6%. Different GI parameters showed associations with better responses.

Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer.

BACKGROUND: Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy regimen to receive either lenvatinib (20 mg, administered orally once daily) plus pembrolizumab (200 mg, administered intravenously every 3 weeks) or chemotherapy of the treating physician's choice (doxorubicin at 60 mg per square meter of body-surface area, administered intravenously every 3 weeks, or paclitaxel at 80 mg per square meter, administered intravenously weekly [with a cycle of 3 weeks on and 1 week off]). The two primary end points were progression-free survival as assessed on blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival. The end points were evaluated in patients with mismatch repair-proficient (pMMR) disease and in all patients. Safety was also assessed. RESULTS: A total of 827 patients (697 with pMMR disease and 130 with mismatch repair-deficient disease) were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients). The median progression-free survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months; hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.50 to 0.72; P<0.001; overall: 7.2 vs. 3.8 months; hazard ratio, 0.56; 95% CI, 0.47 to 0.66; P<0.001). The median overall survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 vs. 12.0 months; hazard ratio for death, 0.68; 95% CI, 0.56 to 0.84; P<0.001; overall: 18.3 vs. 11.4 months; hazard ratio, 0.62; 95% CI, 0.51 to 0.75; P<0.001). Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab and in 72.7% of those who received chemotherapy. CONCLUSIONS: Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. (Funded by Eisai and Merck Sharp and Dohme [a subsidiary of Merck]; Study 309-KEYNOTE-775 ClinicalTrials.gov number, NCT03517449.).

Doxorubicin plus lurbinectedin in patients with advanced endometrial cancer: results from an expanded phase I study.

OBJECTIVE: Second-line treatment of endometrial cancer is an unmet medical need. We conducted a phase I study evaluating lurbinectedin and doxorubicin intravenously every 3 weeks in patients with solid tumors. The aim of this study was to characterise the efficacy and safety of lurbinectedin and doxorubicin for patients with endometrial cancer. METHODS: Thirty-four patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m2 and lurbinectedin 3.0-5.0 mg) and 19 patients in the expansion cohort (doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2). All histological subtypes were eligible and patients had received one to two prior lines of chemotherapy for advanced disease. Antitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4. RESULTS: Median age (range) was 65 (51-78) years. Eastern Cooperative Oncology Group performance status was up to 1 in 97% of patients. In the escalation phase, 4 (26.7%) of 15 patients had confirmed response: two complete and two partial responses (95% CI 7.8% to 55.1%). Median duration of response was 19.5 months. Median progression-free survival was 7.3 (2.5 to 10.1) months. In the expansion cohort, confirmed partial response was reported in 8 (42.1%) of 19 patients (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months. Fatigue (26.3% of patients), and transient and reversible myelosuppression (neutropenia, 78.9%; febrile neutropenia, 21.1%; thrombocytopenia, 15.8%) were the main grade 3 and higher toxicities in the expanded cohort. CONCLUSIONS: In patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42%) and duration of response (7.5 months) were favorable. Further evaluation of doxorubicin and lurbinectedin is warranted in this patient population.

Neural stem cells in the adult olfactory bulb core generate mature neurons in vivo.

Although previous studies suggest that neural stem cells (NSCs) exist in the adult olfactory bulb (OB), their location, identity, and capacity to generate mature neurons in vivo has been little explored. Here, we injected enhanced green fluorescent protein (EGFP)-expressing retroviral particles into the OB core of adult mice to label dividing cells and to track the differentiation/maturation of any neurons they might generate. EGFP-labeled cells initially expressed adult NSC markers on days 1 to 3 postinjection (dpi), including Nestin, GLAST, Sox2, Prominin-1, and GFAP. EGFP+ -doublecortin (DCX) cells with a migratory morphology were also detected and their abundance increased over a 7-day period. Furthermore, EGFP-labeled cells progressively became NeuN+ neurons, they acquired neuronal morphologies, and they became immunoreactive for OB neuron subtype markers, the most abundant representing calretinin expressing interneurons. OB-NSCs also generated glial cells, suggesting they could be multipotent in vivo. Significantly, the newly generated neurons established and received synaptic contacts, and they expressed presynaptic proteins and the transcription factor pCREB. By contrast, when the retroviral particles were injected into the subventricular zone (SVZ), nearly all (98%) EGFP+ -cells were postmitotic when they reached the OB core, implying that the vast majority of proliferating cells present in the OB are not derived from the SVZ. Furthermore, we detected slowly dividing label-retaining cells in this region that could correspond to the population of resident NSCs. This is the first time NSCs located in the adult OB core have been shown to generate neurons that incorporate into OB circuits in vivo.

Generation of a set of isogenic iPSC lines carrying all APOE genetic variants (Ɛ2/Ɛ3/Ɛ4) and knock-out for the study of APOE biology in health and disease.

APOE genotype is the strongest genetic risk factor for Alzheimer's Disease (AD). The low degree of homology between mouse and human APOE is a concerning issue in preclinical models currently used to study the role of this gene in AD pathophysiology. A key objective of ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) project was to generate in vitro models that better recapitulate human APOE biology. We describe a new set of induced pluripotent stem cells (iPSC) lines carrying common APOE variants (Ɛ2, Ɛ3, and Ɛ3/Ɛ4) and a knock-out isogenic to the parental APOE Ɛ4/Ɛ4 line (UKBi011-A).

An olaparib window-of-opportunity trial in patients with early-stage endometrial carcinoma: POLEN study.

OBJECTIVE: Olaparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1, 2, and 3 with potential activity in endometrial cancer (EC). METHODS: In this window-of-opportunity trial, women with operable type 1 EC received olaparib oral tablets (300mg) twice daily for 28days before surgery. The primary objective was to evaluate the effects of olaparib on EC in tissue samples taken at baseline and at treatment completion. Signal of activity was defined as significant changes in the expression of the cell cycle-related proteins cyclin D1, Ki67, and cleaved caspase-3. RESULTS: A total of 31 patients were included in the biomarker analysis. The median time of olaparib exposure was 24 days (1-39). Significant inhibition was found for cyclin D1 (p < 0.01), but not for Ki67 and active caspase 3 immunostaining. PARP-1 levels positively correlated with cyclin D1 levels (rho = 0.661, p = 0.0001). Both PARP-1 and cyclin D1 levels were significantly lower (p = 0.022 and p = 0.004, respectively) in patients with ARID1A[-] tumors than ARID1A[+] tumors. A significant relationship between plasma olaparib concentrations and decreased GLUT1 activity was observed (r = -0.5885; p < 0.05). Drug-related toxicity consisted mostly of gastrointestinal and grade 1 or 2 adverse events. CONCLUSIONS: Olaparib reduced expression of cyclin D1, which positively correlated with PARP-1 levels. This effect was more evident in ARID1A-deficient tumors. Olaparib further induced inhibition of GLUT1 plasma activity. Our findings could have noteworthy implications in predicting which patients with EC would benefit from olaparib-based strategies.

A collection of three integration-free iPSCs derived from old male and female healthy subjects.

Here, we present the characterization of three iPSC lines derived from dermal fibroblasts of old healthy subjects. Fibroblasts were reprogrammed using Sendai viral vectors encoding OCT4, SOX2, KLF4 and c-MYC. The iPSCs expressed endogenous pluripotency markers, could generate the three germ layers (ectoderm, mesoderm and endoderm), maintained a stable karyotype, and were free from Sendai vectors and reprogramming factors. These integration-free iPSCs can serve for establishing control cell cultures in studies searching for phenotypes and mechanisms that could potentially be dysregulated in degenerative diseases.