Metastatic prostate cancer is the most common cancer in males and the fifth cause of cancer mortality worldwide. Despite the major progress in this field, leading to the approval of novel anti-androgens, the prognosis is still poor. A significant number of patients acquire an androgen receptor splice variant 7 (AR-V7), which is constitutively activated and lacks the ligand-binding domain (LBD) while maintaining the nuclear localization signal and DNA-binding domain (DBD). This conformational change, even in the absence of the ligand, allows its retention within the nucleus, where it acts as a transcription factor repressing crucial tumor suppressor genes. AR-V7 is an important oncogenic driver and plays a role as an early diagnostic and prognostic marker, as well as a therapeutic target for antagonists such as niclosamide and TAS3681. Anti-AR-V7 drugs have shown promise in recent clinical investigations on this subset of patients. This mini-review focuses on the relevance of AR-V7 in the clinical manifestations of castration-resistant prostate cancer (CRPC) and summarizes redemptive therapeutic strategies.

Canakinumab is an IL-1β antibody that neutralises the activity of IL-1β. This study examined the efficacy and safety of canakinumab in patients with moderate COVID-19-related pneumonia. This study aimed to evaluate the reduction in duration of hospitalisation with adequate oxygen status. Forty-eight patients with moderate COVID-19-related pneumonia were asked to participate in the prospective case-control study: 33 patients (cases) signed informed consent and received canakinumab (Cohort 1) and 15 patients (Controls) refused to receive the experimental drug and received institutional standard of care (Cohort 2). Hospital discharge within 21 days was seen in 63% of patients in Cohort 1 vs. 0% in Cohort 2 (median 14 vs. 26 days, respectively; p < 0.001). There was significant clinical improvement in ventilation regimes following administration of canakinumab compared with Cohort 2 (Stuart-Maxwell test for paired data, p < 0.001). Patients treated with canakinumab experienced a significant increase in PaO2:FiO2 (p < 0.001) and reduction in lung damage by CT (p = 0.01), along with significant decreases in immune/inflammation markers that were not observed in Cohort 2. Only mild side-effects were seen in patients treated with canakinumab; survival at 60 days was 90.0% (95% CI 71.9–96.7) in patients treated with canakinumab and 73.3% (95% CI 43.6–89.1) for Cohort 2. Treatment with canakinumab in patients with COVID-19-related pneumonia rapidly restored normal oxygen status, decreased the need for invasive mechanical ventilation, and was associated with earlier hospital discharge and favourable prognosis versus standard of care.

The results of the SOLAR-1 and CAPItello-291, highlight the benefit of the ɑ-selective phosphoinositide 3-Kinase Pathway inhibitor (PI3Ki) alpelisib and the AKT inhibitor (AKTi) capivasertib in patients with hormone receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 (HER2)- negative metastatic breast cancer (mBC) that have PIK3CA/AKT1/PTEN tumour alterations. Although effective, these drugs are associated with significant toxicities, which often limit their use, particularly in frail patients. Following the recent incorporation of these agents into clinical practice, and with many others currently in development, significant challenges have emerged, particularly those regarding biomarkers for patient selection. This review will discuss biomarkers of response and their resistance to PI3K/AKT inhibitors (PI3K/AKTis) in HR+/HER- BC in early and advanced settings to ascertain which populations will most benefit from these drugs. Of the biomarkers that were analysed, such as PIK3CA, AKT, PTEN mutations, insulin levels, ^18 F-FDG-PET/TC, only the PIK3CA-mutations (PIK3CA-mut) and the AKT pathway alterations seem to have a predictive value for treatments with alpelisib and capivasertib. However, due to the retrospective and exploratory nature of the study, the data did not provide conclusive results. In addition, the different methods used to detect PIK3CA/AKT1/PTEN alterations underline the fact that the optimal diagnostic companion has yet to be established. We have summarised the clinical data on the approved and discontinued agents targeting this pathway and have assessed the drugs development, successes, and failures. Finally, because of tumour heterogeneity, we emphasise the importance of reassessing the mutational status of PI3KCA in both metastatic tissue and blood at the time of disease progression to better tailor treatment for patients.

Background: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse. Discussion: In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors. Conclusions: Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.

1014 Background: The Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) Palbociclib, Ribociclib and Abemaciclib in combination with Endocrine Therapy (ET) represent the standard-of-care, 1^st line treatment for patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative, advanced Breast Cancer (HR+/HER2- aBC). So far, no large real-world studies have compared the efficacy of the three CDK4/6i in this clinical setting. Methods: The multicenter, population-based study PALMARES-2 evaluated the antitumor efficacy of 1^st line Palbociclib, Ribociclib or Abemaciclib in combination with ET in consecutive HR+/HER2- aBC patients treated in 18 Italian cancer centers between 1^st January 2016 and 1^st September 2023. The primary study endpoint was real-world Progression-Free Survival (rwPFS), as defined as the time interval between ET plus CDK4/6i initiation and disease progression. Multivariate Cox regression model was used to adjust the association between individual CDK4/6i and rwPFS for clinically relevant variables. Results: With a data cut-off date of January 1^st, 2024, we enrolled 1850 patients, 750 (40.6%), 676 (36.5%) and 424 (22.9%) of whom received Palbociclib, Ribociclib and Abemaciclib, respectively. Among 1226 (66.3%) patients with endocrine-sensitive disease, 1087 (89%) received concomitant Aromatase Inhibitors, whereas 441 (70.7%) out of 624 (33.7%) patients with endocrine-resistant disease received concomitant Fulvestrant. Patients treated with Abemaciclib were more likely to have endocrine-resistant disease, liver metastases, lobular tumor histology and lower PgR tumor expression, and less likely to have de novometastatic disease (p<0.001). Median rwPFS in the whole study cohort was 34.9 months (95% CI 32.0-37.4). Abemaciclib and Ribociclib were independently associated with better rwPFS when compared to Palbociclib (Table), whereas Abemaciclib and Ribociclib showed no significantly different efficacy (aHR 0.91, 95% CI 0.70-1.19; p=0.505). Other covariates independently associated with rwPFS are shown (Table). Conclusions: The real-world study PALMARES-2 revealed different antitumor efficacy of individual CDK4/6i in HR+/HER2- aBC patients. Longer follow-up is required to study if Palbociclib, Ribociclib and Abemaciclib are associated with different overall survival. [Table: see text]