The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is changing due to the emergence of new targeted therapies for the treatment of different molecular subtypes. Some biomarkers are described as potential molecular targets different from classic androgen receptors (AR). Approximately 20–25% of mCRPCs have somatic or germline alterations in DNA repair genes involved in homologous recombination. These subtypes are usually associated with more aggressive disease. Inhibitors of the enzyme poly ADP ribose polymerase (PARPi) have demonstrated an important benefit in the treatment of these subtypes of tumors. However, tumors that resistant to PARPi and wildtype BRCA tumors do not benefit from these therapies. Recent studies are exploring drug combinations with phosphatidylinositol-3-kinase (PI3K) or protein kinase B (AKT) inhibitors, as mechanisms to overcome resistance or to induce BRCAness and synthetic lethality. This article reviews various different novel strategies to improve outcomes in patients with prostate cancer.

Background and Aims: Immune checkpoint inhibitors (ICIs) have significantly improved survival rates for patients with metastatic melanoma. However, these treatments can lead to immune-related adverse events (irAEs), including hepatitis. This exploratory study sought to identify tumour single-nucleotide polymorphisms (SNPs) associated with the risk of ICI-induced hepatitis in melanoma patients. Methods: The study cohort comprised 69 patients with malignant melanoma treated with ICIs at several hospitals in Madrid, Spain. DNA was extracted from formalin-fixed paraffin-embedded tumour biopsies and SNP genotyping was conducted using a MassARRAY platform. Results: Significant associations were found between hepatitis risk and 4 of the 20 SNPs examined. A possible risk effect was shown for the variant GABRP SNP alleles rs11743438 and rs11743735. Among patients homozygous for these variant alleles (v/v), significantly higher proportions developed hepatitis, 75% and 71.4%, respectively, compared to 32.8% and 21.4, respectively, not developing hepatitis (p = 0.046; p = 0.013). However, in the same genotype group comparisons, the RGMA SNP rs4778080 seemed to have a protective effect, as 100% of patients who developed hepatitis were not in the v/v group for this allele (p = 0.043). Additionally, in genotype group comparisons wt/wt versus wt/v + v/v, the PACRG SNP rs55733913 was also associated with a higher risk of ICI-induced hepatitis: 66.7% of patients with hepatitis versus 22.8% without hepatitis in genotype group wt/v + v/v (p = 0.041). Conclusions: This exploratory study identifies candidate tumour SNPs as possible biomarkers to predict the risk of ICI-induced hepatitis, warranting their validation in larger patient cohorts.

Naloxegol is a peripherally acting, µ-opioid receptor antagonist for treatment of opioid-induced constipation (OIC). The main objective of this study was to analyze the efficacy of naloxegol in patients with cancer in a real-world prospective study. An observational, one year of follow-up study was conducted in 16 Spanish centers. Patients older than 18 years, with active oncological disease who were under treatment with opioids for pain control were selected. OIC with inadequate response to treatment with laxative (s) was the main diagnostic. The patients received treatment with naloxegol according to clinical criteria. Efficacy was assessed measuring the response rate and symptoms evolution measured by means of PAC-SYM questionnaire. Data of an intermediate analysis after 12 weeks of treatment are analyzed. A total of 126 patients were included in the study and 68 of them in this interim efficacy analysis. About 58.2% were men, with an average age of 61.3 years (34-89). Lung cancer was observed in 35.7%, breast cancer in 15.1% and 8,7% had prostate cancer. About 75.5% had metastases. Naloxegol at doses of 12.5 mg/day was administered to 14.7% and 25 mg/day to 85.3%. Concomitant laxatives were administered to 63.2% of the patients. At 12 weeks, 88.2% of the patients were responders to naloxegol treatment: 80% at doses of 12.5 mg/day, and 89.7% with 25 mg/day. Furthermore, 75% of patients without concomitant laxative treatment were responders with 12.5 mg/day dose of naloxegol and 90.5% were responders with 25 mg/day. A total of 24 adverse reactions appeared in 13.5% of the patients (17/126). The results of this first real-world-data study in patients with cancer confirm the efficacy of naloxegol for the treatment of OIC in this group of patients. Naloxegol is safe and well tolerated in oncologic patients. Kyowa Kirin Farmacéutica, S.L.U. Madrid, Spain. Kyowa Kirin Farmacéutica, S.L.U. A.J. Jiménez López: Full / Part-time employment: Kyowa Kirin Farmacéutica, S.L.U.. I. Huerta González: Full / Part-time employment: Kyowa Kirin Farmacéutica, S.L.U. A. Sanz Yagüe: Full / Part-time employment: Kyowa Kirin Farmacéutica, S.L.U. B. Soler López: Advisory / Consultancy: Kyowa Kirin Farmacéutica, S.L.U. All other authors have declared no conflicts of interest.