Lysodren (mitotane)

3D cell cultures were steroidogenic and demonstrated increased resistance to the gold-standard chemotherapy, mitotane compared to monolayer. The use of these models may lead to an improved understanding of disease pathology and provide a better representative platform for testing and screening of potential therapies.

Given the inconsistent therapeutic benefits and significant side effects associated with the conventional chemotherapy agent, mitotane, and the nascent stage of immunotherapy and targeted treatments, there is an urgent need to identify novel prognostic biomarkers and therapeutic targets in ACC...Immune infiltration analysis further revealed a decrement in CD8+ T-cell infiltration in KPNA2-high cohorts. This study demonstrates the clinical and biological significance of KPNA2 in ACC and suggests that KPNA2 could serve as a promising biomarker for predicting prognosis and immunotherapeutic responses in pediatric and adult ACC patients.

Post-operatively, adjuvant chemotherapy with mitotane was commenced because of histologically high-grade ACC...At both time-points, CTNNB1 mutations consistent with the primary tumor were observed in ctDNA, with the allelic ratio increasing over time from 8% to 27%. In conclusion, monitoring the ctDNA allelic ratio may be useful for evaluating disease progression in advanced ACC.

The recently reported results of the ADIUVO study, although preliminary, discuss the necessity of postoperative therapy with mitotane in patients with low-grade adrenocortical carcinomas (ACCs) after complete resection...Among those, groups (i) and (ii) are more commonly detected in high-grade ACCs but it is also true that specific therapeutic targets based on the molecular characteristics of tumors have remained limited. In addition, possible effects of glucocorticoid excess in functional ACCs on the tumor microenvironment have also been examined, and the utility of immune checkpoint inhibitors is being explored at this juncture.

P=N/A, N=400, Active, not recruiting, University of Wuerzburg | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jun 2024 --> Dec 2024

In addition, we developed 10 ACC patient-derived xenograft (PDX) and two humanized ACC-PDX models to test new therapeutics and examine the mechanism of mitotane action in combination with immunotherapy. These new preclinical models allow us to identify novel targets and test new therapeutics for our patients with adrenal cancer.

P3, N=40, Completed, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia | Unknown status --> Completed | N=240 --> 40 | Trial completion date: Jun 2021 --> May 2024 | Trial primary completion date: Jun 2020 --> Feb 2024

Patients should be diagnosed in large clinical centres with experience in this field. The treatment strategy should be individualised. Genetic testing for TP53 gene mutations is indicated in patients with ACC.

P2, N=3, Completed, M.D. Anderson Cancer Center | Recruiting --> Completed | N=50 --> 3 | Trial completion date: Jan 2028 --> Jul 2024 | Trial primary completion date: Jan 2026 --> Jul 2024

In the setting of metastatic adrenocortical cancer, there are limited therapy options such as mitotane and platinum-based chemotherapy with only low response rates. To the best of our knowledge, this is the first successful use of a long-term two-drug immunotherapy (48 weeks) in a patient with metastatic adrenocortical cancer and high mutational burden. Ipilimumab and nivolumab should be considered as a new therapy option in this patient group.

Our results suggested response to mitotane might be associated with the dependency on lipid metabolism. CYP27A1 and ABCA1 expression could be predictive markers for mitotane response, and disulfiram, niclosamide and bortezomib could be potential therapeutics, both warranting further investigation.

P=N/A, N=400, Active, not recruiting, University of Wuerzburg | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2023 --> Jun 2024

Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids...These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage adrenocortical carcinoma. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors.

Adrenal leiomyosarcoma derived from the smooth muscle wall of a central adrenal vein or its tributaries is rare but should be considered a differential diagnosis in the case of nonfunctioning adrenal tumors extending directly to the inferior vena cava. CT-guided biopsy is considered useful for histopathological diagnosis and clinical management of patients with inoperable advanced adrenal tumors without any hormone excess.

P2, N=30, Enrolling by invitation, National Cancer Center, Korea | Not yet recruiting --> Enrolling by invitation

In addition, our studies revealed an increase in ACSL4 and ABCG2 expression in lowly aggressive H295R cells undergoing early treatment with non-lethal concentrations of mitotane, doxorubicin and cisplatin. The increase in ACSL4 and ABCG2 expression favored tumor cell viability, proliferation and compound efflux, an effect partially offset by ACSL4 and ABCG2 inhibitors. These results provide relevant data on the undesired molecular effects of antitumor drugs and may fuel future studies on patients' early response to antitumor treatment.

Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment.

No differences in PFS and OS curves were observed; the CBR was 75.0% and 60.4%, respectively. (4) The association of EDP-M + megestrol acetate in ACC pts with a low PS is feasible and well tolerated; its efficacy appeared to be non-inferior to EDP-M administered to pts with a good PS.

The response rate of advanced adrenocortical carcinoma (ACC) to standard chemotherapy with mitotane and etoposide/doxorubicin/cisplatin (EDP-M) is unsatisfactory, and benefit is frequently short lived...Here we describe three cases of patients with advanced ACC who were treated with HDR-BT and the CPI pembrolizumab...Sequential combination with CPI therapy may enhance an abscopal antitumoral effect in non-irradiated metastases in ACC. Systematic studies are required to confirm this preliminary experience and to understand underlying mechanisms.

MTT levels reached higher levels at 9 months in ACC patients with high abundance of Proteobacteria, Pseudomonas and Serratia and with low abundance of Bacteroidota, Firmicutes and Streptococcus. These findings are the first indication that human ACCs are characterised by infiltrating bacteria and their specific abundance profile seems to influence the increase in circulating MTT levels at 9 months.

The 5-year survival rate is less than 15% among patients with metastatic disease. In this article, we review the epidemiology and pathogenesis of ACC, the diagnostic procedures, the prognostic classification of ACC, and the treatment options from localized and resectable forms to advanced disease detailing recent therapeutic developments such as immunotherapy and molecularly targeted therapy.

In the two patients experiencing a further rise of mitotanemia, neurological examination was normal but P300 and electroencephalogram were altered. The results of our study highlighted the presence of neurophysiological and neuropsychological abnormalities associated with mitotane values above 18 mg/L.

P3, N=78, Completed, Children's Oncology Group | Active, not recruiting --> Completed

The combination of etoposide, doxorubicin and cisplatin with or without mitotane known as EDP/M, is recommended as first -line regimen based on FIRMACT study. Conclusions The combination of A and T showed promising clinical benefits with moderate toxicities in mACC patients. A+T might become a potential treatment option which need to be further confirmed in the randomized controlled clinical trial.

Post-hoc analyses identified predictors of lack of efficacy (no mitotane, ECOG > 1, ACC 1st diagnosis ≤9 months(mo), lesion size >125 mm, >3 organs involved, lymphopenia >grade 1); C2-post hoc group was created applying these factors. Conclusions EO2401/N was well tolerated generating durable immune responses correlating with efficacy. Based on the greater efficacy in C2-post hoc group a randomized extension is currently recruiting.

Our study suggests that patients with metastatic ACC benefit from inclusion in early clinical trials in second line. As recommended, if a clinical trial is available, it should be the first choice for suitable patients.

Adjuvant mitotane remains the most commonly used adjuvant therapy in ACC based on clinical practice guidelines, though emerging data from ADIUVO trial (mitotane vs observation in low-risk ACC) suggest that mitotane use in low-risk patients may not be needed...A prospective study is needed to study the role of adjuvant radiation in ACC as radiation is expected to help only with local control without impact on distant microscopic metastases. There are no recommendations or published data about using adjuvant immunotherapy in ACC, but this may be a future study after establishing the efficacy and safety profile of immunotherapy in metastatic ACC.

MTT negatively affects the male reproductive system, including changes in the morphology of testicular tissue and reductions in sperm concentration and quality.

P2, N=80, Recruiting, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

A subsequent CT adrenals demonstrated a 12.8 x 13.2 x 10.6cm left adrenal mass and she failed a 1mg overnight dexamethasone suppression test. This is a rare case of ACC secreting multiple hormones, resulting in post-menopausal bleeding and IGF-2 mediated hypoglycaemia.

We have recently proposed a new method analogous to what is established for the anticoagulant warfarin, the time in target range (TTR). Conclusions The present findings show that the patients who are exposed to plasma mitotane >14 mg/L for longer periods have better RFS. These findings provide indirect evidence of the value of adjuvant therapy with mitotane and support the importance of drug monitoring to guide dose adjustment in clinical practice and improve patient outcome.

All 13 patients were taking glucocorticoid replacement therapy and 5 were able to completely withdraw hydrocortisone 39 ± 14.5 months after stopping mitotane treatment. Mitotane can take up to 13 months to become undetectable in patients' plasma after cessation. In our cohort, it is mainly influenced by increased weight but not by duration of exposure to the drug.

We have recently proposed a new method analogous to what is established for the anticoagulant warfarin, the time in target range (TTR). Conclusions The present findings show that the patients who are exposed to plasma mitotane >14 mg/L for longer periods have better RFS. These findings provide indirect evidence of the value of adjuvant therapy with mitotane and support the importance of drug monitoring to guide dose adjustment in clinical practice and improve patient outcome.

No ACC patients studied had been treated with mitotane... Significant differences in plasma steroids were observed in ACC vs ACA patients, with more steroids altered in female patients. Serum steroid profiles, particularly steroid sulfates, might serve as an adjunct, easy to obtain diagnostic tool to differentiate ACA and ACC.

He underwent radiotherapy and mitotane as adjuvant therapies...After six courses of EDP (a combination of etoposide, doxorubicin and cisplatin), CT showed widespread metastases in the retroperitoneum and he chose to receive the best supportive care...Complete resection is needed to improve prognosis and this was not achieved in our case. We therefore recommend careful selection of the operative procedure.

In the real-life setting, we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab-treated patients require confirmation.

In addition, mitotane being the only pharmacological agent approved for the treatment of ACC...Similar findings have been shown in the literature for other 3D cancer cell culture models. All were steroidogenic in nature.ConclusionIn the current study, we successfully developed 3D cell culture models for ACC.This model will be used in the future studies to test novel and traditional therapeutics to test the translational relevance of this model to ACC, as a reliable, animal sparing model.

Additionally, he started IV dexamethasone while inpatient. He was discharged once euvolemic on PO furosemide and follow-up was scheduled with cardiology, oncology, and endocrinology. At discharge, he transitioned to PO hydrocortisone (HC) and was placed on trimethoprim/sulfamethoxazole for PJP prophylaxis, doxazosin, and ketoconazole...Subsequently, he started and failed carboplatin plus etoposide palliative chemotherapy with a continued increase in adrenal mass size. Now, he is on second line pembrolizumab with an ECOG score of 2... ACC is a rare and often aggressive tumor that should be considered in the setting of hypercortisolism and cushingoid features. This is particularly important for patients with a relatively unremarkable history and new onset heart failure with dyspnea on exertion. In these cases, mitotane can be used for hypercortisolism associated with ACC.

No ACC patients studied had been treated with mitotane... Significant differences in plasma steroids were observed in ACC vs ACA patients, with more steroids altered in female patients. Serum steroid profiles, particularly steroid sulfates, might serve as an adjunct, easy to obtain diagnostic tool to differentiate ACA and ACC.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins.

The patient failed a 8mg dexamethasone suppression test with AM cortisol levels of 57.8 mcg/dL (5-25 mcg/dL) with a dexamethasone drug level of 2713 ng/dL (reference range >200 ng/dL), excluding elevated metabolism as cause of failed suppression...Patient was taken off ketoconazole two weeks after prior discharge, not knowing it was temporary treatment for his Cushing's syndrome...Patient was then discharged from our care to an outpatient endocrinologist.This case shows that cortisol levels in ectopic Cushing Syndrome can be effectively lowered through fluconazole treatment. This medication has a more favorable side effect profile than other steroidogenesis inhibitors such as metyrapone and mitotane.Fluconazole monotherapy or dual therapy should be investigated further as a viable option for ectopic Cushing Syndrome therapy prior to bilateral adrenalectomy.

Post-adrenalectomy, the patient's starting dose was 1g mitotane each day with replacement hydrocortisone. While some studies show hypertriglyceridemia secondary to mitotane, others only show elevated cholesterol at 6 and 3 months, respectively. We describe an ACC patient with a history of fatty liver disease and mixed hyperlipidemia who developed severe hypertriglyceridemia and acute pancreatitis leading to multiorgan failure about one month after starting mitotane. This case highlights hypertriglyceridemia as a serious complication of mitotane in a patient with preexisting dyslipidemia.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation.