Development of PARP inhibitors in advanced prostate cancer.

The relatively high prevalence of alterations in the homologous recombination repair (HRR) pathway described in advanced prostate cancer provides a unique opportunity to develop therapeutic strategies that take advantage of the decreased tumor ability to repair DNA damage. Poly ADP-ribose polymerase (PARP) inhibitors have been demonstrated to improve the outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients with HRR defects, particularly in those with BRCA1/2 alterations. To expand the benefit of PARPi to patients without detectable HRR alterations, multiple studies are addressing potential synergies between PARP inhibition (PARPi) and androgen receptor pathway inhibitors (ARSi), radiation, radioligand therapy, chemotherapy, or immunotherapy, and these strategies are also being evaluated in the hormone-sensitive setting. In this review, we summarize the development of PARPi in prostate cancer, the potential synergies, and combinations being investigated as well as the future directions of PARPi for the management of the disease.

Development of PARP inhibitors in advanced prostate cancer Alterations in the mechanisms responsible for repairing damaged DNA are frequently altered in advanced prostate cancer. This provides a unique opportunity to develop therapies that exploit the decreased ability of these prostate tumours to repair DNA. Poly ADP-ribose polymerase (PARP) inhibitors have been successfully used to treat other tumor types with similar deficiencies and recently, multiple studies have demonstrated its efficacy also in prostate cancer, particularly in tumors with BRCA1/2 alterations. To expand the benefit of PARPi to patients without detectable DNA repair alterations, multiple studies are addressing potential synergies between PARP inhibition (PARPi) and androgen receptor pathway inhibitors (ARSi), radiation, radiopharmaceuticals, chemotherapy and immunotherapy in different disease stages. In this review, we summarize the development of PARPi in prostate cancer, the potential synergies and combinations being evaluated as well as the future directions of PARPi for the management of the disease.

Systemic Immune-Inflammation Index in Patients Treated With First-Line Immune Combinations for Metastatic Renal Cell Carcinoma: Insights From the ARON-1 Study.

BACKGROUND: Systemic treatment with immune combinations is the gold standard for metastatic renal cell carcinoma (mRCC) worldwide. The systemic immune-inflammation index (SII) is a prognostic marker for several types of malignant neoplasms, including mRCC, in the era of tyrosine kinase inhibitor (TKI) treatment. Data regarding the prognostic value of the SII in patients with mRCC treated with immunotherapy are scarce and controversial.  METHODS: We retrospectively collected the data of patients with mRCC from 56 centers in 18 countries. SII (Platelet × Neutrophil/Lymphocyte count) was calculated prior to the first systemic treatment and cut-off was defined by a survival receiver operating characteristic (ROC) analysis. The primary objective of our retrospective study was to assess the outcomes of patients treated with first-line immunotherapy.  RESULTS: Data from 1034 mRCC patients was collected and included in this analysis. The SII cut-off value was 1265. After a follow-up of 26.7 months, and the overall survival (OS) and progression-free survival (PFS) were 39.8 and 15.7 months, respectively. According to SII (low vs. high), patients with low-SII had longer OS (55.7 vs. 22.2 months, P < .001), better PFS (20.8 vs. 8.5 months, P < .001), and higher overall response rate (52 vs. 37%, P = .033). CONCLUSION: A high SII is associated with poor oncological outcomes in patients with mRCC. SII could be an easily accessible prognostic indicator for use in clinical practice.

Genomic Landscape in Prostate Cancer in a Latin American Population.

PURPOSE: This study aims to describe genomic characteristics of patients with metastatic prostate cancer (mPC). PATIENTS AND METHODS: This study is a retrospective, multicenter cohort study of patients with mPC and reports on genomic testing. Patients were included from 12 academic centers in five countries. RESULTS: A total of 349 patients with PC were included in this study. Most patients (209, 59.9%) were de novo metastatic. Genomic analysis was performed in 233 (66.6%) patients in the metastatic castration-resistant prostate cancer (mCRPC) setting, and only 115 (32.8%) patients had a tumor evaluation in the metastatic hormone sensitive prostate cancer scenario. The evaluation of somatic and/or germline mutations was performed through multigene panel analyses in 290 (83.09%) patients, and next-generation sequencing of BRCA1 and BRCA2 genes was performed in 59 (16.91%) patients. Analyzing the mCRPC subgroup, with a median follow-up of 15.6 months (IQR, 14-19.06), the median progression-free survival (PFS) was not reached (NR) and the PFS at 16 months was 58.7% (95% CI, 50.8 to 67.8). When comparing patients with BRCA mutations with those who are not BRCA-mutated in the mCRPC scenario, the median PFS was NR (95% CI, 14 to NR) and 26.3 months (95% CI, 16.7 to 36.5; P = .2), respectively. Two of six patients with BRCA mutations were treated with targeted therapies (poly-ADP-ribose polymerase inhibitors). CONCLUSION: Our study, to the best of our knowledge, represents one of the larger data sets for somatic testing in patients with PC in Latin America (LATAM). It adds valuable information to the growing body of knowledge about the genomic landscape of advanced PC in real-world daily practice scenarios in LATAM countries, which are not always well-represented in large-scale randomized clinical trials.