Expert Opinion on Investigational Drugs

Potential of IMNN-001 in epithelial ovarian cancer: assessment of clinical findings

IMNN-001 is designed for local and durable delivery of a pluripotent anti-tumor cytokine, IL-12, using an expression plasmid and a synthetic lipopolymer delivery system. IMNN-001, delivered intraperitoneally in combination with chemotherapy, is currently in a Phase 3 trial for the front-line treatment of advanced epithelial ovarian cancer. This report details IMNN-001 preclinical and clinical development, demonstrating local and durable production of IL-12, minimal systemic exposure and manageable safety profile, as well as its antitumoral effects in a total of six completed trials in ovarian cancer. In the OVATION-2 Phase 2 randomized trial, neo- and adjuvant chemotherapy combined with IMNN-001 produced a numerical 13 month increase in overall survival, with even greater benefit in tumors that lacked DNA homologous repair activity. In translational studies, IMNN-001-induced changes in the tumor microenvironment are consistent with the observed induction of IL-12 and IFN-γ levels at the tumor site and support the hypothesis that IMNN-001 treatment alters the tumor microenvironment in favor of broad immune stimulation and inhibition of immunosuppressive mechanisms. IMNN-001 gene therapy could add clinically meaningful IL-12-driven immunotherapy to newly diagnosed ovarian cancer patients. IMNN-001 holds promise for synergistic combinations with immunotherapies requiring intrinsic immune activity.

Advances in the treatment of platinum resistant epithelial ovarian cancer: an update on standard and experimental therapies

KIF18A inhibition and its rising role in cancer therapy trials: from bench to bedside

Poly (ADP-ribose) polymerase (PARP) as target for the treatment of epithelial ovarian cancer: what to know

Poly (ADP-ribose) polymerase (PARP) inhibitors are being developed in maintenance and recurrence treatment settings of epithelial ovarian cancers (EOCs) with BRCA 1-2 gene mutation. PARP inhibitors are the first example of drugs targeting the loss of a gene suppressor: they block base-excision repair in the cancer cells, which have lost homologous recombination due to BRCA-mutation, resulting in loss of DNA repair and cell death, also known as synthetic lethality. This article provides an overview of PARP inhibitors in OC treatment and also an extensive section on the combined strategies of PARP inhibitors, including approved as well as currently investigated drugs. It also offers a section on the use of predictive biomarkers for PARP inhibitors treatment. Ongoing trials, including novel combinations, are discussed. In recent years, there is increasing evidence that PARP inhibitor therapy can have life-long percussion in the treatment of EOC, even if some questions have to be solved yet, such as its use in combination therapy, the possibility to retreat with a PARP inhibitor, and finally how to overcome a resistance mechanism to this therapy. In this way, PARP inhibitors can obtain an important role in making a personalized therapeutic program in the case of first-line, neoadjuvant, platinum-sensitive, and resistant high-grade serous OC treatment.

Oregovomab: an investigational agent for the treatment of advanced ovarian cancer

PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers

Poly (ADP-ribose) polymerase inhibitors (PARPis) are an exciting class of agents that have shown efficacy, particularly for BRCA-mutant triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC). However, most patients who receive PARPi as their standard of care therapy inevitably develop resistance and this underscores the need to identify additional targets that can circumvent such resistance. Combination treatment strategies have been developed in preclinical and clinical studies to address the challenges of efficacy and resistance. This review examines completed or ongoing clinical trials of PARPi mono- and combination therapies. PARPi monotherapy in HER2 negative breast (HR+ and TNBC subtypes) and ovarian cancer is a focal point. The authors propose potential strategies that might overcome resistance to PARPi and discuss key questions and future directions. While the advent of PARPis has significantly improved the treatment of tumors with defects in DNA damage and repair pathways, careful patient selection will be essential to enhance these treatments. The identification of molecular biomarkers to predict disease response and progression is an endeavor.

HPV-induced cancers: preclinical therapeutic advancements

High-risk HPV infections are related to several epithelial cancers. Despite the availability of prophylactic vaccines, HPV infections are still responsible for about 5% of all human malignancies worldwide. While therapeutic vaccines are ongoing clinical trials, genotoxic agents and surgical interventions represent current clinical treatments, with no specific anti-HPV drugs yet available in the clinics. We offer a comprehensive report of small molecules in preclinical studies proposed as potential anticancer agents against HPV-driven tumors. Given the importance of HPV oncoproteins for cancer maintenance, particularly E6 and E7, we present a classification of both non-targeted and targeted agents, with a further subdivision of the latter into two categories according to their either direct or indirect activity against viral protein functions. Prophylactic vaccines can prevent the insurgence of HPV-related cancers, but have no effect against preexisting infections. Moreover, their high cost, genotype-restricted effect and the growing worldwide distrust for vaccines make the availability of a specific drug an unmet medical need. Different viral early proteins emerge as ideal candidates for drug development. We highlight the most promising strategies and address future challenges in this field to herald the prospect of a specific therapeutic regimen against HPV-related cancers.

Tumor immunology and immunotherapy for endometrial cancer

Recent clinical trials show the efficacy of immune checkpoint inhibitors (ICIs) or a combination of ICI and poly (ADP-ribose) polymerase (PARP) inhibitors for advanced or recurrent endometrial cancer. However, the basis for such treatment effects remains unclear, hindering the advancement of personalized therapy. This review includes a detailed interpretation of subgroup analysis data from phase III clinical trials for endometrial cancer evaluating the efficacy of chemotherapy plus ICIs (NRG-GY018, RUBY, AtTEnd, KEYNOTE-B21) or chemotherapy plus ICI with/without olaparib (DUO-E). We focused on the relationship between obesity, the effect of PARP inhibitors, and tumor immunity in endometrial cancer, searched for relevant literature published from 2000 to 2024 in PubMed, and conducted a narrative review. Chemotherapy plus ICI is appropriate for dMMR. Chemotherapy plus ICI and PARP inhibitor may be appropriate for TP53abn type or serous carcinoma because PARP inhibitor enhances the efficacy of ICI by activating the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway. Obese patients may benefit more from ICIs, and this appears to cause the variation in efficacy between regions/countries. Administration for measurable disease appears important to increase the effect of ICIs. Diet and exercise may also be important factors.

Experimental and new investigational drugs for the treatment of uterine fibroids

Uterine fibroids, the most prevalent benign tumors among reproductive-age women, pose treatment challenges that range from surgical interventions to medical therapies for symptom control. Progestins and estroprogestins effectively manage uterine bleeding by suppressing dysfunctional endometrium over fibroids. While GnRH agonists represent a crucial milestone in symptom treatment, their prolonged use results in menopausal-like symptoms and irreversible bone mineral density loss. Advancements in understanding fibroid pathophysiology have prompted the exploration of new compounds to overcome current therapy limitations. This manuscript offers an updated overview of investigational drugs for symptomatic uterine fibroids. Despite ulipristal acetate's well-established efficacy as a selective progesterone receptor modulator (SPRM) in fibroid treatment, its prescription has declined due to the rare but severe risk of liver damage. Oral GnRH antagonists, like elagolix, relugolix, and linzagolix, with their novel pharmacodynamic properties, are gaining traction in fibroid management, inducing a dose-dependent reduction in circulating sex hormone levels. Ongoing research on natural compounds, such as vitamin D and epigallocatechin gallate (EGCG), presents emerging options for treating uterine fibroids. This evolving landscape reflects the ongoing efforts to improve therapeutic outcomes for individuals with symptomatic uterine fibroids.

Prexasertib: an investigational checkpoint kinase inhibitor for the treatment of high-grade serous ovarian cancer

Introduction Patients with high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and current chemotherapy regimens for treating advanced disease are far from satisfactory. Prexasertib (LY2606368) is a novel checkpoint kinase inhibitor (CHK) under investigation for the treatment of HGSOC. Data from a recent phase II trial showed promising efficacy and safety results for treating wild-type BRCA HGSOC. Areas covered This article reviews the available data on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of prexasertib in the treatment of HGSOC. Expert opinion Until now, prexasertib demonstrated clinical activity in phase I and II clinical trial for treating wild-type BRCA HGSOC, whereas its promising efficacy as monotherapy and combined with olaparib in BRCA-mutated HGSOC has been preliminary evidenced only in phase I studies. Compared to other drugs of the same class, prexasertib showed a better tolerability profile, causing moderate hematological toxicity. Further studies are needed to confirm efficacy and safety profiles of prexasertib in combined regimens. New early clinical trials may investigate prexasertib administered with programmed cell death ligand 1 (PD-L1) and PI3 K inhibitors due to the preclinical evidence of a synergic action.