Adrenocortical carcinomas (ACCs) are rare and aggressive malignancies of adrenal cortex, associated with largely unknown mechanisms of biological development and poor prognosis. Currently, mitotane is the sole approved drug for treating advanced adrenocortical carcinomas (ACCs) and is being utilized more frequently as postoperative adjuvant therapy. Although it is understood that mitotane targets the adrenal cortex and disrupts steroid production, its precise mechanism of action requires further exploration. Additionally, mitotane affects cytochrome P450 enzymes, causes the depolarization of mitochondrial membranes, and leads to an accumulation of free cholesterol, ultimately resulting in cell death. Many patients treated with mitotane develop disease progression over time, underlying the need to understand the mechanisms of primary and acquired resistance. In this manuscript, we provide an overview on the intracellular mechanisms of action of mitotane, exploring data regarding predictive factors of response and evidence associated with the development of primary and acquired resistance mechanisms. In this discussion, mitotane is considered a real target therapy.

Background: Advanced adrenocortical carcinoma (ACC) remains a challenging malignancy with limited therapeutic options. Multi-kinase inhibitors (MKIs), either alone or in combination with immuno-oncology (IO) agents, have been investigated in recent single-arm clinical trials and retrospective series. Methods: We conducted a systematic review and single-arm meta-analysis of studies evaluating MKIs in advanced ACC. Objective response rate (ORR) and disease control rate (DCR) were pooled using random-effects models for single-arm proportions. Overall survival (OS) and progression-free survival (PFS) were summarized descriptively due to limited variance data. Subgroup analyses compared MKI monotherapy versus MKI + IO combinations, and meta-regression was performed to assess the impact of prior mitotane exposure. Results: Eleven studies (n = 208 patients) were included. The pooled ORR was 21% (95%CI, 11–36%), and the DCR was approximately 57%. Subgroup analysis revealed a higher ORR with MKI + IO regimens (26%; 95%CI, 12–48%) compared to MKI monotherapy (15%; 95%CI, 3–47%). Median OS ranged from 5.4 to 30.6 months, and PFS from 2.8 to 13.3 months, both favouring MKI + IO combinations. Meta-regression identified prior mitotane exposure as a significant predictor of ORR (p = 0.0279), particularly within the MKI + IO subgroup. Conclusions: MKI-based regimens, especially when combined with IO, demonstrate promising efficacy in advanced ACC, a disease with few established second-line options. While limited by the non-comparative design of available studies, these findings support further investigation in prospective, randomized clinical trials.

Background/Objectives: Androgen deprivation therapy (ADT) is the mainstay of prostate cancer treatment, especially in advanced disease. In particular, the gonadotropin-releasing hormone agonists (aGnRH) reduce the production of gonadotropin and, therefore, of testosterone. In about 10% of patients, the non-pulsatile stimulation of GnRH receptor initially causes a surge in LH and testosterone, defined as the “flare-up phenomenon”, leading to increased bone pain, spinal cord compression, bladder outlet obstruction and cardiovascular issues. To mitigate this effect, combining a first-generation antiandrogen agent (FGA) with aGnRH is recommended. However, second-generation anti-androgens, such as apalutamide, bind selectively and irreversibly to the androgen receptor (AR), exhibiting a more efficient inhibition of the AR pathway. Methods: This is a descriptive retrospective study of 27 patients (pts) with mHSPC, treated at a single center (“Santa Maria delle Grazie” Hospital in Pozzuoli, ASL Napoli 2 Nord, Italy) between June 2022 and April 2024. Patients received apalutamide monotherapy for 14 days followed by continuous combination with aGnRH plus apalutamide. Serum PSA and testosterone levels were measured at baseline, at day 14 (after 13 days of apalutamide monotherapy), at day 28 (after an additional 15 days of apalutamide plus a aGnRH), and at day 60. Results: PSA levels decreased from a mean of 45.2 (±63.1) ng/mL at baseline to a mean of 12.6 (±23.4) ng/mL at day 14 and to 3.3 ng/mL (±6.0) at day 28 of treatment. After 14 days of apalutamide monotherapy, 21 patients (77.8%) achieved a >50% PSA reduction and 4 (14.8%) a >90% PSA reduction. The number of patients with undetectable PSA was one (3.7%) at day 14, two (7.4%) at day 28, and nine (33.3%) at day 60. The mean serum testosterone levels were 6.56 (±4.46) ng/mL at baseline, 6.58 (±4.42) ng/mL at day 14, and 2.40 (± 3.38) ng/mL at day 28. No significant difference in PSA and testosterone level reduction during treatment emerged between subgroups of patients with low- vs. high-volume disease. Conclusions: Apalutamide alone is a viable option for mitigating the flare-up phenomenon, avoiding first generation anti-androgen therapy, and it can achieve rapid and deep biochemical control.

The benefit of adjuvant mitotane after complete resection of low-risk adrenocortical carcinoma (ACC) remains uncertain. The ADIUVO randomized trial was underpowered due to low event rates. We conducted a reconstructed individual patient data (IPD) analysis to provide a comprehensive reassessment of treatment effects. IPD were reconstructed from published Kaplan-Meier curves of the ADIUVO randomized trial and its parallel prospective observational cohort using the Guyot algorithm. Overall survival (OS) and recurrence-free survival (RFS) were analysed using Cox proportional hazards models, restricted mean survival time (RMST), and accelerated failure time (AFT) models. Pooled analyses were stratified by study design. Exposure-response analyses evaluated therapeutic mitotane levels (≥14 mg/L) and early target attainment. The reconstructed randomized cohort included 91 patients (18 RFS events; 19 deaths). In intention-to-treat analysis, no clear evidence of a benefit with mitotane was observed for RFS (HR=0.99, 95%CI 0.39-2.50; p = 0.99) or OS (HR=0.98, 95%CI 0.40-2.42; p = 0.97). RMST differences at 60 months were negligible (-0.05 months for RFS; -0.19 months for OS). In the observational cohort (n = 95), no significant differences were observed for RFS (HR=0.90, 95%CI 0.32-2.47) or OS (HR=0.75, 95%CI 0.31-1.84). Pooled analysis (n = 186; 39 OS events; 33 RFS events) likewise showed no clear evidence of improved OS (HR=0.86, 95%CI 0.45-1.61) or RFS (HR=1.05, 95%CI 0.53-2.08). Exposure-based analyses did not demonstrate a consistent survival advantage associated with therapeutic drug levels or early target attainment, although these analyses were limited by small sample sizes. Across complementary modelling approaches, no clear evidence of a clinically meaningful survival benefit with adjuvant mitotane was observed. While small effects cannot be definitively excluded, the overall consistency of findings suggests that any potential benefit is likely marginal. Active surveillance therefore represents an evidence-aligned management strategy in this population.

Adrenocortical carcinomas (ACCs) are rare adrenal tumors that occur in hereditary syndromes or sporadically. Even in sporadic cases, somatic alterations in known susceptibility genes are often detected, emphasizing the growing role of genomic profiling. Recent evidence indicates that ACCs vary in their pathogenetic mechanisms, biochemical phenotype, metastatic potential, and prognosis. While surgery remains the primary treatment for localized ACCs, multiple therapeutic options exist for advanced or metastatic disease, although robust prospective data supporting a genomic profiling-oriented approach are still lacking. To enhance personalized management and improve outcomes in this molecularly complex disease, routine genetic testing for germline mutations along with comprehensive genome profiling for somatic mutations and cluster identification should become standard clinical practice. This review summarizes current evidence on ACC diagnosis and treatment, underscoring the need for a more personalized, cluster-based approach in clinical practice.

Cisplatin-based neoadjuvant chemotherapy (NAC) improves survival in muscle-invasive urothelial cancer (MIUC), yet pathological complete response (pCR) is achieved in a minority of patients. Relative dose intensity (RDI) is a potentially modifiable determinant of chemotherapy efficacy, but its impact during NAC in MIUC remains unexplored. This multicentre retrospective study included patients with MIUC treated with cisplatin-gemcitabine NAC followed by radical cystectomy. RDI was calculated from original administration records and categorised as ≥ 85% versus <85%. The primary endpoint was pCR (ypT0N0M0). Secondary endpoints included overall survival (OS) and event-free survival (EFS). A total of 330 patients were included; 66% maintained RDI≥85%. Overall pCR rate was 25.2%. Patients with RDI≥85% achieved higher pCR rates compared with those with RDI<85% (29.7% vs 16.2%; p = 0.008). RDI≥85% remained independently associated with pCR in multivariable analysis (OR = 2.10; p = 0.032). Preserved RDI was also associated with improved EFS (HR = 0.65; p = 0.039) and OS (HR = 0.53; p = 0.026) at univariate analysis. Achievement of pCR was strongly associated with superior EFS (HR = 0.23; p < 0.001) and OS (HR = 0.35; p = 0.009). Preservation of cisplatin RDI≥85% during NAC is independently correlated with higher pCR rates and associated to a better survival trend in MIUC. Optimisation of chemotherapy delivery represents a clinically actionable strategy to enhance neoadjuvant efficacy.