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PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying the same mechanism of action are currently under investigation. Despite the success of these targeted agents, the increasing use of PARPis in clinical practice for the treatment of different tumors raised the issue of PARPis resistance, and the consequent disease relapse and dismal prognosis for patients. Several mechanisms of resistance have been investigated, and ongoing studies are currently focusing on strategies to address this challenge and overcome PARPis resistance. This review aims to analyze the mechanisms underlying PARPis resistance known today and discuss potential therapeutic strategies to overcome these processes of resistance in the future.

Background High grade serous ovarian cancer (HGSOC) is highly lethal, partly due to chemotherapy resistance and limited availability of targeted approaches. Cyclin dependent kinases 12 and 13 (CDK12/13) are promising therapeutic targets in human cancers, including HGSOC. Nevertheless, the effects of their inhibition in HGSOC and the potential synergy with other drugs are poorly known. Methods We analyzed the effects of the CDK12/13 inhibitor THZ531 in HGSOC cells and patient-derived organoids (PDOs). RNA sequencing and quantitative PCR analyses were performed to identify the genome-wide effects of short-term CDK12/13 inhibition on the transcriptome of HGSOC cells. Viability assays with HGSOC cells and PDOs were performed to assess the efficacy of THZ531 as single agent or in combination with clinically relevant drugs. Results The CDK12 and CDK13 genes are deregulated in HGSOC and their concomitant up-regulation with the oncogene MYC predicts poor prognosis. HGSOC cells and PDOs display high sensitivity to CDK12/13 inhibition, which synergizes with drugs in clinical use for HGSOC. Transcriptome analyses revealed cancer-relevant genes whose expression is repressed by dual CDK12/13 inhibition through impaired splicing. Combined treatment with THZ531 and inhibitors of pathways regulated by these cancer relevant genes ( EGFR , RPTOR , ATRIP ) exerted synergic effects on HGSOC PDO viability. Conclusions CDK12 and CDK13 represent valuable therapeutic targets for HGSOC. We uncovered a wide spectrum of CDK12/13 targets as potential therapeutic vulnerabilities for HGSOC. Moreover, our study indicates that CDK12/13 inhibition enhances the efficacy of approved drugs that are already in use for HGSOC or other human cancers.

Cervical cancer (CC) is still characterized by a poor prognosis despite the progress made in its treatment in recent years. Although immunotherapy has improved outcomes for advanced/recurrent disease, there is a significant gap in addressing patients’ needs when they progress after platinum and immunotherapy treatments. In this setting, traditional chemotherapy showed limited effectiveness. In this context, antibody–drug conjugates (ADCs) emerged as a promising tool within targeted cancer therapies. Tisotumab vedotin (TV), an ADC targeting tissue factor, represents the first ADC approved by the US Food and Drug Administration for the treatment of recurrent or metastatic CC with disease progression on or after chemotherapy. In phase I–III published trials, TV has already demonstrated an advantage in terms of objective response rate (17.8%–54.4%) and progression-free survival (3.1–6.9 months) in patients who progressed to the first-line standard therapy. Data concerning the addition of TV to platinum/pembrolizumab first-line chemotherapy are still under analysis and strongly expected. However, several questions are still unresolved: (1) the identification of the most suitable timing for ADCs administration in the treatment sequence of advanced/recurrent CC; (2) the evaluation of combination therapies as a tool to minimize the emergence of resistant clones and to enhance overall effectiveness; and (3) the assessment of tolerability and correct management of special toxicities (e.g. ocular and neurological adverse events). In the near future, an improvement in patient selection via biomarker-driven strategies should be crucial for optimizing both treatment benefits and maintaining an acceptable toxicity profile.

Introduction/BackgroundNeoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), has been shown to be not oncologically inferior to primary debulking surgery for patients affected by advanced epithelial ovarian cancer (EOC). However, 20% of patients don’t respond and therapeutic options are limited. The genomic landscape could, at least partially, explain this phenomenon. By correlating mutational profiles with clinical outcomes, we aimed at identifying genomic features of resistance to platinum-based chemotherapy.MethodologyFPG500 (IRB 3837) is a comprehensive cancer genome profiling programme at Fondazione Policlinico Agostino Gemelli IRCCS. An evaluation of 523 genes (TSO500HT, Illumina) is provided. All EOC patients addressed to NACT and enrolled in FPG500 were included. Response to NACT was scored following the chemotherapy response score (CRS): no/minimal tumor response (CRS1), partial response (CRS2), and total response (CRS3). Age, residual tumour at IDS, and stage were also considered.ResultsAt data cut-off of the 9th of January 2023, 96 EOC patients were included in this preliminary analysis. 85 patients had at least one genomic alteration (78%). The overall mean of alterations was 1.75 (SD=1.37). CCNE1 amplifications were associated with older age (17% age < 64 years vs 26.5% > 64 years), and worse CRS (24% CRS 1–2 vs 15% CRS 3), similar to PIK3CA (mainly single nucleotide variants [SNVs] or insertion/deletions [Indels]) (37% CRS 1–2 vs 19% CRS 3). MYC amplifications and PIK3CA alterations were associated with a more advanced stage (respectively 37.5% and 39% stage IV vs 27% and 25% stage III). However, MYC was associated to with a better response to NACT (28% CRS 1–2 vs 42% CRS 3).ConclusionCCNE1, MYC and PI3KCA genomic alterations seem to be associated with stages and response to chemotherapy, however, a sample size of 365 patients is required to obtain statistical significance. The enrollment is ongoing and results are expected in 2025.DisclosuresThe authors declare no disclosures.

ObjectivesThe treatment choice in locally advanced cervical cancer (LACC) ranges from concurrent chemoradiation to neoadjuvant chemotherapy followed by radical surgery (RS); however, the rates of 5-year Progression Free Survival (PFS) (55%) and Overall Survival (OS) (63%) remain largely disappointing. Up to 92% of CC display high PD-L1 levels; therefore, the addition of anti-PD-1 immunotherapy may improve LACC prognosis. MITO CERV 3 trial aims at exploring the addition of Pembrolizumab to standard chemotherapy in PD-L1 positive patients (PDL1>1%).MethodsMITO CERV 3 is a single arm multicenter phase II trial evaluating the role of Pembrolizumab in combination with chemotherapy in stage IB2-IIB (according to FIGO 2009 classification) CC patients. Patients will receive 3 cycles of neoadjuvant (NAD) Carboplatin AUC 5 + Paclitaxel 175 mg/mq + Pembrolizumab 200 mg q21, followed by RS in non-progressing patients. After surgery, only patients with clinicopathological high risk factors will receive 3 further cycles of adjuvant chemotherapy in combination with Pembrolizumab, followed by Pembrolizumab alone as maintenance until progression or unacceptable toxicity or for up to 35 cycles. The primary endpoint will be PFS. An exploratory analysis on tumor biopsies before and after NAD will be performed, to identify immunogenic and genetic markers of responsiveness or resistance to NAD treatment.ResultsTrial in progress: there are no available results at the time of submission.ConclusionsTrial in progress: there are no available conclusions at the time of submission.

Introduction/BackgroundDespite the majority of BRCA1/2 mutated (BRCA1/2mut) ovarian carcinoma (OC) experience remarkably prolonged survival, the reason why some BRCA1/2mut carriers experience poor prognosis remains unclear, particularly for those patients who experience recurrence within 12 months following platinum-based chemotherapy. Furthermore, the advent of maintenance therapies from first-line settings, particularly PARP inhibitors (PARPi), has shifted the landscape of relapse, potentially reducing the incidence of true platinum-resistant recurrences. The identification of genetic and epigenetic differences may help to cluster patients at diagnosis and predict platinum response.MethodologyWe retrospectively enrolled 20 BRCA1/2mut FIGO stage III-IV HGSC patients, who received primary debulking surgery and adjuvant chemotherapy, regardless of maintenance therapy, between 2018 and 2022 at Fondazione Policlinico Universitario Agostino Gemelli. All samples were used for RNA extraction (QIAGEN RNeasy FFPE Kit). RNA concentrations were determined by the 260 nm absorbance, and purity was assessed based on the 260/280 nm ratio using NanoDropTM 2000 Spectrophotometer (ThermoFisher Scientific). RNA quality was checked by electrophoresis (Agilent TapeStation). The median RNA Integrity Number (RIN) was 6 (range 5.8–7.4) and therefore ribosomal depletion was performed. Indexed libraries were then processed (paired-end sequencing, 50M depth). EdgeR in R studio will be used for count files; both EnrichR and ShinyGO will be used for Gene Ontology. Additionally, part of the samples were tested for 523 multipanel genes’ set through Next Generation Sequencing (NGS).ResultsWe aim at identifying genes that may be uniquely over- or under-expressed among BRCA1/2mut patients with extreme prognostic outcomes. Additionally, we intend to integrate RNA sequencing data with those from NGS.ConclusionThis integrated approach will enable us to describe molecular signatures that not only distinguish between patients with favorable and unfavorable prognoses but also enhance our understanding of the underlying mechanisms driving these diverse clinical outcomes.DisclosuresR.E. reports Honoraria/consultation fees from GSK; C.M. reports Honoraria/consultation fees from AstraZeneca, Pharmamar, GSK, MSD, Menarini; A.F. reports Honoraria/consultation fees from AstraZeneca, MSD, Johnson & Johnson; G.S reports Honoraria/consultation fees from Covidien AG, AstraZeneca, MSD, Olympus Europa, Baxter Healthcare, GlaxoSmithKline, Intuitive Surgical Inc.; C.M. reports Honoraria/consultation fees from MSD, Illumina, GSK, Vedeva, Altems.Abstract #705 Figure 1

ObjectiveCorrelation between BRCA1/2 (BRCA) pathogenic variants and the response to poly (ADP-ribose) polymerase inhibitors (PARPi) has been recognized in patients with ovarian cancer. Moreover, data on the clinical implications of variants of unknown significance are lacking. The aim of this study was to evaluate differences in survival outcomes in patients with BRCA variants of unknown significance, mutated, and wild type relapsed ovarian cancer treated with PARPi.MethodsPatients with ovarian cancer whose somatic BRCA testing was available and who were receiving PARPi as maintenance treatment at the first recurrence between January 2014 and January 2021 were included in the present study and analyzed. Patients were divided into three groups according to BRCA mutational status (variant of unknown significance, mutated, and wild type). Progression-free survival was assessed in each study group.ResultsOf 67 patients identified, 20 (29.9%), 24 (35.8%), and 23 (34.3%) had BRCA variant of unknown significance, mutated, and wild type, respectively. Patients received PARPi as maintenance treatment at the time of the first relapse after a complete response or partial response to platinum-based chemotherapy without differences in the previous platinum-free interval among the analyzed groups. The median progression-free survival of patients with BRCA mutation was significantly longer than for those with BRCA wild type or variant of unknown significance (not reached vs 4 months vs 7 months, respectively; p<0.001). Additionally, no significant difference was found between patients with BRCA wild type and BRCA variant of unknown significance (p=0.50).ConclusionOur study suggests that carriers of BRCA variant of unknown significance have survival outcomes comparable to patients with BRCA wild type and shorter progression-free survival than women harboring BRCA pathogenic variants.

ObjectivesPlatinum resistant ovarian cancer (OC) patients have a poor prognosis, and few treatment options are available. Preclinical and clinical data demonstrated that the combination PARP inhibitors with immune checkpoint inhibitors could have a synergistic antitumor activity in this setting of patients. MITO 33 trial will assess the hypothesis that the combination niraparib/dostarlimab therapy is effective in increasing overall survival (OS), progression free survival (PFS) and time to first subsequent therapy with respect to chemotherapy alone.MethodsRecurrent platinum resistant OC will be randomized 1:1 to receive: -Arm A: pegylated liposomal doxorubicin 40 mg/mq d1q28, weekly paclitaxel 80 mg/mq d1,8,15q28, gemcitabine 1000 mg/mq d1,8,15q28 or topotecan 1.25 mg/mq d1–5q21; -Arm B: dostarlimab 500 mg every 3 weeks for 4 cycles, then 1000 mg every 6 weeks + niraparib 300 mg or 200 mg daily. Patients will be stratified according to homologous recombination deficiency status (positive vs negative) evaluated with Foundation One CDx LOH test, PD-L1 status, previous immunotherapy, previous PARPi treatment and Bevacizumab therapy. Endpoints Primary Endpoint: OS Secondary Endpoints: PFS; Time to First Subsequent Therapy and Objective Response Rate; Safety and Tolerability of Dostarlimab plus Niraparib Exploratory Objective: relationship between PD-L1 expression and the efficacy of niraparib/dostarlimab treatment; relationship between lymphoid or myeloid-derived suppression cells or T-regulatory cells (T-regs) and response to niraparib/dostarlimab treatmenResultsTrial in progress: there are no available results at the time of submissionConclusionsTrial in progress: there are no available conclusions at the time of submission.

Introduction/BackgroundState of the art therapy for recurrent platinum sensitive and PARP inhibitors (PARPi) naïve ovarian cancer (OC) patients includes platinum-based chemotherapy (carboplatin single agent or combined with paclitaxel, gemcitabine or pegylated liposomal doxorubicine) followed by PARPi as maintenance. Aim of the present study is to assess the predictive role of different platinum-based CT combinations on the effectiveness of PARPi in patients with platinum sensitive recurrent OC.MethodologyThis retrospective observational study included relapsed OC patients that received platinum-containing regimen followed by PARPi as maintenance, at the time of first or subsequent platinum sensitive recurrence. Primary endpoints were progression free survival (PFS) and overall survival (OS).ResultsAmong 519 patients enrolled, 16.2% (84) received carboplatin as monotherapy and 80% (415) a doublet of platinum-based CT. Specifically, 16.4% (86) patients were treated with platinum-paclitaxel, 30.6% (159) with platinum-pegylated liposomal doxorubicin (PLD) and 32.8% (170) with platinum-gemcitabine. No statistical difference was found in terms of PFS between patients treated with the platinum-monotherapy and those treated with a doublet (mPFS 13.6 vs 14.4 months), but patients who received doublet had longer OS (mOS 29.7 vs 50.8 months; HR 0.6, p=0.03). According to specific CT doublets, no statistical difference was found in terms of PFS and OS, but a trend toward an increase in PFS was reported in patients treated with platinum-PLD. Specifically, a longer PFS was found in patients treated with platinum-PLD compared to platinum-gemcitabine (mPFS 17.2 vs 13 months) (figure 1).ConclusionRegardless of the type of associated drug or whether monotherapy is used, platinum remains the drug that most correlates with the effectiveness of PARP inhibitors. However, the combination platinum-PDL seems to be the most advantageous, especially when compared to platinum-gemcitabine.DisclosuresThe authors have the following conflict of interests: F.S.: GSK, MSD, Astrazeneca, Roche; C.D.A.: Novartis, Daiichi Sankyo, GILEAD, GSK, Astrazeneca, Roche, Pfizer, Seagen; G.S.: Clovis, MSD, Tesaro, Johnson D.L.: Clovis, MSD, GSK, Gemnab, Astrazeneca, Immunogen, Oncainvest, Pharmamar. The other authors declare have no conflict of interest.Abstract 526 Figure 1

Introduction/BackgroundDespite impressive progression free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer (OC), concerns about their effect on post-progression treatment outcomes have recently arisen, particularly in the relapsed setting. Mechanisms of overlapping resistance between PARPi and platinum have been suggested, and optimal therapy after PARPi progression is unknown. The aim of this study is to describe outcomes of subsequent chemotherapy after niraparib progression in recurrent platinum sensitive OC, focusing both on platinum rechallenge and no platinum-based chemotherapy.MethodologyIn this exploratory analysis, data from high-grade serous or endometrioid OC patients who received subsequent chemotherapy after progression to niraparib in the recurrent setting in 17 MITO centers, were collected and analyzed. Primary endpoint of this analysis was overall response rate (ORR).ResultsTwo hundred and thirty-one patients with progressive disease to niraparib were included in this study: 101 patients had a platinum free interval (PFI) of less than 6 months and 130 patients a PFI > 6 months. Among these, 136 women (59%) were evaluable for response to the subsequent chemotherapy after progression on niraparib. In the group of patients with PFI < 6 months weekly paclitaxel was the most frequently administered regimen (37.3%) and ORR was 10.4%, while the ORR in the group of patients with PFI > 6 months was 26.3% (2 CR and 14 PR) and clinical benefit rate (CBR) was 47.6%. Fifty-five patients in this group received platinum-based chemotherapy and reported an ORR of 29%. The remaining 16 women with PFI >6 months were treated with pegylated liposomal doxorubicin (PLD) in combination with trabectedin: no responses were reported in this cohort of patients.ConclusionPatients who experienced disease progression following niraparib treatment showed a poor response to subsequent platinum-based chemotherapy, even when progression occurred more than 6 months after completion of their penultimate platinum-based chemotherapy.DisclosuresThe authors declare no disclosures.