Prostate cancer remains a leading cause of cancer-related mortality in men, with advanced stages posing significant treatment challenges due to high morbidity and mortality. Among genetic alterations, TP53 mutations are among the most prevalent in cancers and are strongly associated with poor clinical outcomes and therapeutic resistance. This review investigates the role of TP53 mutations in prostate cancer progression, prognosis, and therapeutic development. A comprehensive analysis of preclinical and clinical studies was conducted to elucidate the molecular mechanisms, clinical implications, and potential therapeutic approaches associated with TP53 alterations in prostate cancer. TP53 mutations are highly prevalent in advanced stages, contributing to genomic instability, aggressive tumor phenotypes, and resistance to standard treatments. Emerging evidence supports the utility of liquid biopsy techniques, such as circulating tumor DNA analysis, for detecting TP53 mutations, providing prognostic value and facilitating early intervention strategies. Novel therapeutic approaches targeting TP53 have shown promise in preclinical settings, but their clinical efficacy requires further validation. Overall, TP53 mutations represent a critical biomarker for disease progression and therapeutic response in prostate cancer. Advances in detection methods and targeted therapies hold significant potential to improve outcomes for patients with TP53-mutated prostate cancer. Further research is essential to integrate TP53-based strategies into routine clinical practice.

Survival outcomes after radical cystectomy (RC) for bladder cancer (BCa) have not improved in recent decades; nevertheless, RC remains the standard treatment for patients with localized muscle-invasive BCa. Identification of the patients most likely to benefit from RC only versus a combination with systemic therapy versus systemic therapy first/only and bladder-sparing is needed. This systematic review and meta-analysis pools the data from published studies on blood-based biomarkers to help prognosticate disease recurrence after RC. A literature search on PubMed and Scopus was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Articles published before November 2022 were screened for eligibility. A meta-analysis was performed on studies investigating the association of the neutrophil-to-lymphocyte ratio (NLR), the only biomarker with sufficient data, with recurrence-free survival. The systematic review identified 33 studies, and 7 articles were included in the meta-analysis. Our results demonstrated a statistically significant correlation between elevated NLR and an increased risk of disease recurrence (HR 1.26; 95% CI 1.09, 1.45; p = 0.002) after RC. The systematic review identified various other inflammatory biomarkers, such as interleukin-6 or the albumin-to-globulin ratio, which have been reported to have a prognostic impact on recurrence after RC. Besides that, the nutritional status, factors of angiogenesis and circulating tumor cells, and DNA seem to be promising tools for the prognostication of recurrence after RC. Due to the high heterogeneity between the studies and the different cut-off values of biomarkers, prospective and validation trials with larger sample sizes and standardized cut-off values should be conducted to strengthen the approach in using biomarkers as a tool for risk stratification in clinical decision-making for patients with localized muscle-invasive BCa.

BACKGROUND: [¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) has demonstrated clinical efficacy in metastatic androgen pathway modulator-naïve (mAPMN) and metastatic castration-resistant prostate cancer (mCRPC), however treatment responses remain heterogeneous. PURPOSE: To evaluate the prognostic value of PSMA PET-derived imaging biomarkers and genomic alterations in relation to biochemical response and clinical outcomes in systemic therapy-naïve patients with mAPMN PCa receiving [¹⁷⁷Lu]Lu-PSMA RLT as first-line systemic therapy. METHODS: Systemic therapy-naïve patients with mAPMN PCa treated exclusively with [¹⁷⁷Lu]Lu-PSMA-RLT were retrospectively analyzed. Standardized uptake value (SUV) parameters (SUVmax, SUVmean, SUVpeak) and PSMA total tumor volume (PSMA-TTV) were derived from baseline and post-treatment [68Ga]Ga-PSMA-11 PET scans, with imaging response defined as a ≥30% reduction. Prostate-specific antigen (PSA) response, PSA-PFS and androgen deprivation therapy (ADT)-free survival were assessed. Available germline and somatic genomic alterations were analyzed for associations with outcomes. RESULTS: 26 patients were analyzed. Reductions ≥30% in SUVmax and PSMA-TTV were associated with prolonged PSA-PFS (27.1 vs. 9.4 months, p=0.01; 27.1 vs. 5.5 months, p< 0.001, respectively) and ADT-free survival (39.0 vs. 19.9 months, p=0.03; 23.9 vs. 13.8 months, p=0.028, respectively). In multivariable analysis, ΔPSMA-TTV ≥30% was independently associated with prolonged PSA-PFS (HR 0.23, 95% CI 0.08-0.68; p=0.008). Of 17 genomically profiled patients, nine had somatic alterations, most frequently involving TP53, MYC, NF1. Patients with altered DNA damage repair (DDR) pathway had lower baseline PSA (0.78 vs. 12.3 ng/mL; p=0.03) and SUVpeak (7.9 vs. 16.7; p=0.03). No other associations with genetic alteration status were observed. CONCLUSIONS: In systemic therapy-naïve patients with mAPMN PCa, reductions of ≥30% in SUVmax and PSMA-TTV following PSMA-RLT were associated with favorable outcomes, with ΔPSMA-TTV independently associated with prolonged PSA-PFS. PSMA PET-derived parameters may support treatment response assessment, whereas no prognostic association with genomic alterations was identified in this cohort.