177Lu-PSMA therapy in metastatic prostate cancer: An updated review of prognostic and predictive biomarkers.

177Lu-PSMA has been approved for the treatment of PSMA-positive metastatic castration-resistant (mCRPC) patients who progressed to androgen receptor pathway inhibitors (ARPIs) and taxane-based chemotherapy. However, a higher proportion of patients do not respond to this type of radioligand therapy (RLT). To date, there is a lack of validated prognostic and predictive biomarkers for 177Lu-PSMA therapy in prostate cancer. Several studies have investigated the prognostic and predictive role of clinical and molecular factors and also the metabolic features of PET imaging. In this review, we aim to take stock of the current scenario, focusing on new emerging data from retrospective/prospective series and clinical trials. Given the high costs and the possibility of primary resistance, it seems essential to identify clinical and molecular characteristics that could allow clinicians to choose the right patient to treat with 177Lu-PSMA. Biomarker-based clinical trials are urgently needed in this field.

Concomitant Administration of VEGFR Tyrosine Kinase and Proton Pump Inhibitors May Impair Clinical Outcome of Patients With Metastatic Renal Cancer.

INTRODUCTION: The administration of proton pump inhibitors (PPIs) is a common practice to reduce gastro-esophageal adverse events associated with drug treatments but may impair absorption and exposure to oncology drugs. This study investigated the effect of concomitant administration of PPIs and pazopanib, sunitinib and cabozantinib on survival of patients with metastatic clear cell renal carcinoma (mRCC). PATIENTS AND METHODS: Total 451 patients receiving pazopanib, sunitinib and cabozantinib as first line treatment were enrolled in this retrospective study. Patients were defined as "no concomitant PPIs (PPI-)" if no PPIs were administered during TKIs, and as "concomitant PPIs (PPI+)" if the administration of PPIs was at least 75% of the time during which TKIs were given. RESULTS: Eighty patients administered pazopanib were PPI- and 86 PPI+; no difference in PFS was observed (10.7 vs. 11.9 months, P = .79). If patients were stratified as short (n = 89) and long (n = 77) responders, there was a significant difference in terms of PFS in PPI+ (n = 47) versus PPI- (n = 30) in long responders, being 24.7 versus 38 months (P = .04), respectively. In the sunitinib cohort, no significant difference of PFS in PPI+ (n = 102) versus PPI- (n = 131) was found, being 11.3 versus 18.1 months, respectively (P=0.15). In the cabozantinib cohort, there was a statistically significant difference in PFS of PPI+ versus PPI- (6 months vs. not reached, P = .04). No correlation with adverse events was found. CONCLUSIONS: This study demonstrates an association between PPIs and impaired PFS in mRCC patients given pazopanib and cabozantinib and recommends caution on their concomitant use.

Inherited Mutations in DNA Damage Repair Genes in Italian Men with Metastatic Prostate Cancer: Results from the Meet-URO 10 Study.

Background: The prevalence of pathogenic germline mutations in DNA damage repair (gDDR) genes in the Italian population is unknown. Objective: In this prospective multicenter cohort study, we evaluated the prevalence of gDDR alterations in the Italian population affected by metastatic prostate cancer (mPCa) and analyzed the impact on response to therapy, survival, and time to castration resistance. Design setting and participants: In an observational prospective trial, 300 consecutive Italian mPCa patients, enrolled in the Meet-Uro-10 trial from three academic Italian centers, were recruited between 2017 and 2019 and were screened for gDDR mutations in 107 genes. Outcome measurements and statistical analysis: The primary endpoint was to assess the prevalence of gDDR mutations in the Italian population of patients with mPCa. The secondary endpoints included the association of gDDR subgroups with metastatic onset, Gleason score, and time to castration resistance. Results and limitations: We identified 297 valuable patients. Forty-six patients had a pathogenic/likely pathogenic variant (15.5%, 95% confidence interval: 11.4-19.6): the more frequent was gBRCA2 found in nine cases (3%), followed by gATM in five cases (1.7%). In patients without mutations, longer median overall survival was observed with the sequence docetaxel-androgen receptor signaling inhibitor (ARSI) than with the sequence ARSI-docetaxel (87.9 vs 42 mo, p = 0.0001). In a univariate analysis, the median time to castration resistance in gDDR mutated patients was 19.8 mo, versus 23.7 mo in no mutated patients (p = 0.024). There were no associations of gDDR subgroups with metastatic onset and Gleason score ≥8. In our cohort, variants of unknown significance in gDDR genes were found in 80 patients and might have a prognostic relevance. Conclusions: The study reported the prevalence of gDDR in the Italian population. The presence of gBRCA2 mutations correlates with a shorter time to the onset of castration resistance disease. Patient summary: The prevalence of gBRCA2 in the Italian population is 3%, which is similar to that in the Spanish population, identifying similarities between people of the Western Mediterranean area.