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A Systematic Review of Published Clinical Trials in the Systemic Treatment of Adrenocortical Carcinoma: An Initiative Led on Behalf of the Global Society of Rare Genitourinary Tumors
Tiago Costa de Padua,1 Laura Marandino,1 Daniele Raggi,1 Julie Hallanger-Johnson,2 Alexander Kutikov,3 Philippe E. Spiess,4 Andrea Necchi1,5
Abstract
Adrenocortical carcinoma (ACC) is a very rare endocrine cancer and is associated with a poor prognosis. There is a paucity of randomized clinical trials for this rare disease. We aimed to perform a systematic review of the literature on systemic therapy options in different stages of ACC. A systematic review was performed using Pubmed and Embase databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 24 trials of systemic therapy in the treatment of ACC were identified and included in this review. Only one clinical trial in the adjuvant setting was identified, the negative phase III trial ADIUVO, which tested mitotane in low to intermediate-risk ACC patients. In the treatment of advanced ACC, cisplatin-based chemotherapy was evaluated in small and non-randomized phase II trials, and response rates ranged from 21% to 53.5%. The phase III trial FIRM- ACT compared etoposide, doxorubicin, cisplatin, and mitotane versus treatment with streptozotocin and mitotane and showed no difference in OS, but higher RR and PFS were reported with the multi-drug regimen. Six clinical trials of immunotherapy and seven studies of targeted therapy in advanced ACC were included, with modest activity and no phase 3 trials were identified. Treatment recommendations of ACC are based on retrospective and small studies with limited systemic therapy options. International and multi-center collaboration is essential to expand clinical research and improve outcomes.
Clinical Genitourinary Cancer, Vol. 21, No. 1, 1-7 @ 2022 Elsevier Inc. All rights reserved. Keywords: Systemic therapy, Adrenocortical carcinoma, Immunotherapy, Chemotherapy, Targeted therapy
Introduction
Adrenocortical carcinoma (ACC) is a very rare endocrine cancer of the adrenal cortex. According to the Surveillance Epidemiol- ogy and End Results analysis, the estimated incidence of ACC is approximately one case per million people per year.1,2 Most cases are sporadic, but around 10% of patients are associated with heredi- tary syndromes, including Li-Fraumeni, multiple endocrine neopla- sia, and Beckwith-Wiedemann. A study in southern Brazil revealed a 10 to 15 times higher incidence in the pediatric population, likely
correlated to a tumor protein 53 (TP53) germline mutation in this specific population.3
Despite its rarity, ACC is associated with a poor prognosis, and 20% to 50% of the patients are diagnosed with advanced or metastatic disease, with overall survival (OS) of less than one year.4,5 Treatment recommendations are mainly based on expert consensus and retrospective studies, with few randomized clinical trials for this rare disease. In this systematic review, we summarize the systemic therapy options in different stages of ACC.
1 Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, MI, Italy
2 Endocrine Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL
3 Division of Urology and Urologic Oncology, Fox Chase Cancer Center, Philadelphia, PA
4 Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 5Vita-Salute San Raffaele University, Milan, MI, Italy
Submitted: Sep 14, 2022; Revised: Oct 12, 2022; Accepted: Oct 20, 2022; Epub: 23 October 2022
Address for correspondence: Tiago Costa de Padua, MD, MSc, Department of Medical Oncology, IRCCS San Raffaele Hospital, Via Olgettina, 60, 20132, Milano, Italy E-mail contact: costadepadua.tiago@hsr.it
Material and Methods
A systematic review was performed in July 2022 using Pubmed and Embase databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.6 The following terms combined with Boolean operators (AND, OR, NOT) were used: adrenocortical carcinoma, ACC, and adrenal cortex carcinoma. The following filters were used: clinical trials and human studies. Search results were restricted to the English language. PRISMA flow diagram in Figure 1.
Identification of studies via databases and registers
Identification
Records identified from Medline search (n = 40)
Records identified from Embase search (n = 209)
Records duplicates removed (n = 20)
Screening
Reports screened (n = 229)
Reports excluded (n =200)
Paediatric (n =13)
Not systemic therapy (n =31)
Not adrenocortical carcinoma (n =81)
Retrospective (n = 23) Review, case report or comments (n= 48) Pre-clinical (n= 1) Trial in progress (n = 3)
Reports assessed for eligibility (n = 38)
Included
Studies included in review (n = 25)
Eligibility Criteria
All prospective clinical trials, either comparative or non- comparative, of systemic therapy in the treatment of ACC in adults were included. We excluded observational studies, guide- lines, case reports, meta-analyses, editorials, reviews, and articles not published in English. The outcomes of interest were overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), OS, toxicity profile, and analysis of QoL.
Data Extraction
After removing duplicates, 2 independent reviewers selected the articles and extracted the necessary information, including
name, year, sample size, drugs, sex, age, oncologic outcomes, and adverse events (AE) rates. When available, hazard ratios (HRs) and 95% confidence intervals (CIs) associated with PFS and OS were collected.
Results
A total of 24 trials of systemic therapy in the treatment of ACC were identified and included in this review, including 1 clinical trial in the adjuvant setting,7 10 trials of chemotherapy in advanced disease, 8-17 6 clinical trials of immunotherapy in advanced ACC18-23 and seven studies of targeted therapy in advanced ACC.24-30
Adjuvant Trials
Mitotane is an adrenolytic drug, a derivative of the insecti- cide dichlorodiphenyltrichloroethane (DDT), with a mechanism of action not well characterized resulting in a strong inhibition of steroidogenesis. The recommendation for adjuvant use is based on retrospective studies with conflicting results. The strongest evidence stems from a multicenter, retrospective study published in 2007 with 177 ACC patients who had undergone radical surgery with 47 patients receiving post-resection mitotane. The recurrence-free survival (RFS) was significantly prolonged with the use of mitotane compared to an Italian and German cohort of patients treated with surgery alone.31 A systematic review and meta-analysis included five retrospective studies and demonstrated that adjuvant mitotane significantly improved RFS (HR = 0.62; 95%CI, 0.42-0.94; P < .05) and OS (HR = 0.69; 95%CI, 0.55-0.88, P < . 05), suggesting a potential benefit with this strategy.32
The only randomized study identified was the phase III ADIUVO trial, which evaluated the efficacy of mitotane as adjuvant therapy in low to intermediate-risk ACC patients (stage I-III ACC, R0 surgery, and Ki-67 ≤ 10%). Results were recently presented, and adjuvant mitotane did not increase the RFS for this specific population. However, very few patients with Stage III disease were included, calling into question the applicability to this group of patients. Interestingly, patients in this trial exhibited a 5-year RFS of 75%, better than expected and historical controls.7 An ongoing phase 3 trial is recruiting high-risk patients (stage III-IV) after surgery to receive mitotane with or without cisplatin-based chemotherapy with a primary endpoint of RFS and an estimated number of patients of 240 (NCT03583710).
Advanced Disease- Chemotherapy Trials
A total of 11 clinical trials testing chemotherapy in the treatment of advanced or metastatic ACC were included; Table 1 summa- rizes the findings. Cisplatin-based chemotherapy was evaluated in small and non-randomized phase II trials, and ORRs ranged from 21% with docetaxel plus cisplatin to 53.5% with a four-drug regimen (Cisplatin + etoposide + doxorubicin + mitotane). Just one randomized phase 3 trial was identified. The phase III FIRM- ACT trial compared etoposide, doxorubicin, cisplatin, and mitotane versus treatment with streptozotocin and mitotane in the treatment of 304 patients with metastatic ACC. There was no difference in OS, likely due to the crossover design of the study, but higher ORR (23 vs. 9%) and PFS were reported with the multi-drug regimen. Rates of serious adverse events were similar in the two arms.15
Studies evaluating second-line chemotherapy have shown limited efficacy, including streptozotocin or the combination of gemcitabine plus capecitabine/ 5-FU, with or without mitotane.13 Cabazitaxel was assessed in a single-institution, nonrandomized phase 2 study as second or third-line therapy, after progression to cisplatin-based chemotherapy plus mitotane. There was no confirmed response among 25 enrolled patients, presenting a DCR after 4 months of 24%, PFS 1.5m, OS 6m.16
Immunotherapy Trials
Immune checkpoint inhibitors (anti-PD1/PDL1) have been tested in the treatment of metastatic ACC with notably long-
term disease control in a small subset of patients (Table 2). Pembrolizumab was evaluated in a small study with 39 patients with advanced ACC and led to an ORR of 23% and a DCR of 52%. MSI-H/MMR-D was detected in 6 patients (16%), of whom 2 had a partial response.21 The CA209-538 trial, a prospective multicenter clinical trial, assessed the efficacy of Nivolumab plus ipilimumab in patients with advanced rare cancers and included 6 cases of advanced ACC. The disease control rate for this popula- tion was 66%, and microsatellite instability was identified in the 2 patients with confirmed responses.22 Nivolumab was also tested in a phase 2 trial with only 10 patients, but the results showed minimal efficacy as monotherapy.19 The phase 1b JAVELIN trial, testing avelumab in solid tumors refractory to conventional treatments, included a cohort of 50 ACC patients after failure to platinum-based chemotherapy. In this pretreated population, the RR was only 6%, and DCR was 42%.18
Targeted Therapy
Several trials have evaluated the use of targeted therapy in the treatment of unselected patients with advanced ACC (Table 3). However, the initial results are disappointing, and no drugs have been approved by regulatory agencies since the approval of mitotane. Cixutumumab, an anti-IGF1R antibody, and linsitinib, an oral TKI targeting IGF1R and insulin receptor, showed limited efficacy in clinical trials, with a very low DCR and without survival improvement.29,30 VEGF targeted therapy, including sunitinib, and dovitinib has also been tested as systemic therapy for advanced ACC; however, without activity.25,28 One particularly important discov- ery in the sunitinib trial was that mitotane in combination with sunitinib showed a diminished response, most likely due to the cytochrome P450/3A4 induction by mitotane.25
Discussion
Here, we provide a comprehensive review of the systemic therapy options for the management of adrenocortical carcinoma based on available scientific evidence and published clinical trials. We found several phase I and II clinical trials with different strategies, but only 1 randomized phase III clinical in the adjuvant setting and 2 phase III trials in the management of advanced/ metastatic ACC with published results. Performing clinical trials in ACC has been a challenge in the last decades due to patient scarcity and limited treatment options, as illustrated by the low number of clinical trials and enrolled patients.
The standard of care for suspected localized ACC is upfront open adrenalectomy and loco-regional lymphadenectomy with negative margins. An important aspect is to avoid rupture of the tumor capsule and en bloc resection of macroscopically invaded adjacent organs should be considered to achieve R0 resection. Retrospec- tive studies have suggested that laparoscopy adrenalectomy (LA) is associated with a higher risk of local recurrence and peritoneal spread. Guidelines from ESES/ENSAT consider LA as an alterna- tive approach only for suspected ACC with a diameter of less than 6cm, without lymph node involvement or local invasion. Patients should be referred to high-volume centers and managed with a multi-disciplinary approach.33
| Author | Year | Phase | Treatment | N | Line | FU | RR | DCR | PFS/ TTP |
|---|---|---|---|---|---|---|---|---|---|
| Decker RA | 1991 | II | Mitotane or Doxorubicin | 52 | 1L or 2L (after progression to mitotane) | NR | 22% / 19% | NR | NR |
| Bonacci A | 1998 | II | Cisplatin + Etoposide + mitotane | 18 | 2L (after progression mitotane) | NR | 33% | NR | NR |
| Williamson SK | 2000 | II | Cisplatin + Etoposide followed by mitotane | 45 | 1L or 2L (after progression to mitotane) | NR | 11% | NR | NR |
| Baudin E | 2002 | prospective | Irinotecan | 12 | 2L or later | NR | 0 | 25% | NR |
| Berruti A | 2005 | II | Etoposide + Doxorubicin + Cisplatin + mitotane | 72 | 1L | NR | 48.6% | NR | 9.1 |
| Sperone P | 2010 | II | Gemcitabine plus metronomic 5-fluorouracil or capecitabine + mitotane | 28 | 2L or 3L | NR | 7% | 46.3% | 5.3 |
| Berruti A | 2012 | II | Paclitaxel + sorafenib | 25 | 2L or 3L | NR | premature | interruption of the trial | |
| Fassnacht M | 2012 | III | Mitotane + Etoposide + Doxorubicin + Cisplatin vs Mitotane + streptozotocin | 304 | 1L | NR | 23.2% vs. 9.2% P<0.001 | 58.3% vs 31.4% | 5.0 vs. 2.1 HR 0.55; 95% CI, 0.43 to 0.69 P<0.001 |
| Lagana M | 2022 | II | Cabazitaxel | 25 | 2L, after CT | NR | 0% | 36% | 1.5 (0.3-7) |
| Urup T& | 2013 | II | Docetaxel + Cisplatin | 19 | 1L | NR | 21% | 53% | 3 |
CI= confidence interval; CT= chemotherapy; DCR= disease control rate; FU= follow-up; HR= hazard ratio; N= number; NR= not reported; PFS= progression-free survival; RR= response rate
| Author | Year | Phase | Treatment | N | Line | Follow-up | RR | DCR | PFS |
|---|---|---|---|---|---|---|---|---|---|
| Le Torneau C | 2018 | 1b | Avelumab | 50 | 2L | 16.5 | 6% | 48% | 2.6 (95% CI, 1.4 to 4.0) |
| Carneiro BA | 2019 | II | Nivolumab | 10 | 2L or later | 4.5 | 10% | 30% | 1.8 |
| Habra MA | 2019 | II | Pembrolizumab | 16 | 2L | NR | 14% | 64% | NR |
| Raj N | 2020 | II | Pembrolizumab | 39 | any line | 17.8m | 23% | 52% | 2.1 (95% CI, 2.0 to 10.7) |
| Klein O | 2020 | II | Nivolumab + Ipilimumab | 6 | any line | 14.7 | 33% | 66% | NR |
| Baudin E | 2022 | I/II | EO2401 (EO) + Nivolumab | 33 | 1L or 2L | NR | 12 | 36 | 1.9 (0.4-7.6+) |
CI= confidence interval; DCR= disease control rate; N= number; NR= not reported; PFS= progression-free survival; RR= response rate
| Author | Year | Phase | Treatment | N | Line | FU | RR | DCR | PFS |
|---|---|---|---|---|---|---|---|---|---|
| Smith DC | 2020 | I | Nevanimibe HCl | 63 | 2L | NR | 0 | 27% | NR |
| Kroiss M | 2012 | II | Sunitinib | 38 | 2L | 15.4 | 0 | 17% | 2.8 (95% CI 80-85 d) |
| Haluska P | 2010 | I | Figitumumab | 14 | 2L | NR | 0 | 57% | NR |
| Fassnacht M | 2015 | III | Linsitinib (OSI-906) vs placebo | 139 | 2L or later | NR | 3.3% vs 0 | 32.2% vs 34.7% | 1.46 vs. 1.53 (HR 0.83, 95% CI 0.56 to 1.21; P = . 30) |
| García-Donas J | 2014 | II | Dovitinib | 17 | 1L | 5.2 | 0 | 35 | 1.8 (95% CI, 1,35-2,25) |
| Lerario AM | 2014 | II | Cixutumumab and Mitotane | 20 | 1L | NR | 5 | 40 | 1.5 |
| Naing A | 2013 | I | Cixutumumab and Temsirolimus | 26 | 2L or later | NR | NR | 42% | NR |
CI = confidence interval; CT= chemotherapy; DCR= disease control rate; FU= follow-up; HR= hazard ratio; N= number; NR= not reported; PFS= progression-free survival; RR= response rate
Adjuvant treatment with mitotane monotherapy is recommended by guidelines only for high-risk patients after surgery (stage III disease, R1 resection, or Ki-67 > 10%).34 This recommendation is based on previous retrospective studies, suggesting a possible benefit in recurrence-free survival. The only randomized phase 3 trial in this setting assessed adjuvant mitotane in low to intermediate-risk ACC patients (stage I-III ACC, R0 surgery, and Ki-67 ≤ 10%) and failed to show benefit of this strategy. Based on these results and the relatively good prognosis of these subgroups of patients, adjuvant mitotane should not be used routinely. When indicated, mitotane blood monitoring is recommended, and the treatment duration should be of at least 2 years but not more than 5 years.35 The consensus panel from ENSAT suggests considering adjuvant radiotherapy in patients with R1 resection or stage III disease as individualized basis therapy.36 If indicated, it should be offered in addition to mitotane. This recommendation is based on small retro- spective studies without a clear benefit of this approach. There is no evidence of adjuvant cytotoxic chemotherapy as adjuvant therapy.
In this review, no clinical trials in neoadjuvant setting were identi- fied. This strategy is not recommended by guidelines unless in the context of clinical trials. A small single-center series reported outcomes of 53 patients with ACC candidates for surgery, of whom 15 were considered borderline resectable and treated with neoadjuvant therapy (mitotane monotherapy or combined with cytotoxic chemotherapy). The response rate was 38.5 %, and other 7 patients achieved stable disease. The median DFS for the patients treated with neoadjuvant followed by surgery was 28.0 months, suggesting a possible benefit of this strategy.37 Cases of locally advanced disease should be discussed in multidisciplinary tumor boards, and neoadjuvant treatment can be considered if cytore- duction is needed for surgery. However, this indication is based on a very weak level of evidence, and prospective studies are required.
Unresectable or metastatic ACC is associated with a very poor prognosis. Systemic therapies are scarce, with small benefits and high toxicity incidence. The scientific evidence consists mainly of retrospective studies and small non-randomized trials. Mitotane is the only approved drug by FDA and EMA and can be recom- mended either alone or in combination with cytotoxic chemother- apy. According to guidelines, mitotane monotherapy is recom- mended for patients with a low volume of disease and a limited number of metastatic sites or patients with later recurrence after surgery.35,36 Available evidence reports low response rates but a benefit in controlling hormonal secretion.
Mitotane should be combined with cytotoxic cisplatin-based chemotherapy in patients with extensive and rapidly progressive disease. Pre-clinical data suggest synergism of this combination, as mitotane increases the cytotoxic activity of chemotherapy agents in vitro, through action possibly as an antagonist of the multidrug resistance (MDR) protein. The phase III FIRM-ACT trial estab- lished the combination of cisplatin, etoposide, doxorubicin, and mitotane as the preferred option for first-line treatment.
The control of excess hormone secretion is an important consid- eration. Debulking surgery and metastasectomy can be considered for selected patients after multidisciplinary discussion, especially for
patients with > 90% removable disease and functional tumors.33 Ablative treatment with SBRT, thermal ablative therapies, or liver- directed therapy should be indicated case-by-case as part of an individualized strategy. Consolidative surgery with resection of residual disease should also be considered in selected patients with a deep and sustained response after systemic therapy. This recommen- dation is based on previous reports that showed favorable long-term tumor control and survival with this strategy.12
Recently, several phase I and II trials have tested targeted therapy immune checkpoint inhibitors (ICIs) as a treatment alternative for advanced ACC, but with disappointing results and limited efficacy. Based on available phase II results, pembrolizumab is indicated as a treatment option in consensus and NCCN guidelines. Interest- ingly, evidence from previous studies suggests that glucocorticoid- producing tumors might be less responsive to ICI compared to non-functioning tumors, probably related to immune suppres- sion induced by cortisol.20 Combination strategies to enhance the antitumor effects of ICI should be further explored, includ- ing the role of association with mitotane. Ongoing trials are evaluating the combination of immunotherapy and anti-VEGF targeted therapy. The phase II trial ACCOMPLISH is assessing the efficacy of Pembrolizumab Plus Lenvatinib (NCT05036434) in Korean patients, and the Spanish phase II trial CABATEN is testing cabozantinib plus atezolizumab in the treatment of advanced endocrine tumors, including ACC (NCT04400474).
Recently, molecular profiling of ACC tumors has identified potential targets for precision medicine. An integrative and exten- sive molecular analysis of 45 ACCs, identified alterations in known driver genes, including TNNB1, TP53, CDKN2A, RB1, MEN1, ZNRF3, DAXX, TERT, and MED12. The findings were validated in an independent cohort of 77 ACCs, from centers participants of ENSAT.38 The molecular landscape was further characterized by the TCGA study, analyzing 91 ACC cases. Alterations in p53 apopto- sis/Rb1 cell cycle and/ or Wnt/b-catenin pathway were found in more than 40% of cases. At least 1 potential driver gene alteration was identified in 69% of tumors, with potentially actionable alter- ations.39 Blood-based next-generation sequencing (NGS) in 120 patients with ACC, detected at least 1 somatic alteration in 80% of the patients, including TP53 (52%), EGFR (23%), CTNNB1 (18%), MET (18%), and ATM (14%). Notably, actionable alter- ations were observed in 56 patients (47%), including EGFR, BRAF, ATM, and MET.40
Despite the increased use of genomic profiling (GP) as a tool for prognostic information and as a guide for precision medicine, the scientific evidence of genetic-driven therapy efficacy is very limited in the treatment of advanced ACC, with just series and case reports. Ongoing umbrella trials are testing targeted therapy guided by genetic testing (NCI-MATCH) in different tumor types, and may help to define the role of precision medicine in rare tumors. Meanwhile, guidelines from the European Society of Endocrinol- ogy Clinical recommend GP tests only in the context of research.36 NCCN guidelines recommend genetic counseling, testing for inher- ited genetic syndromes (germline), and considering tumor MSI, MMR, and TMB testing using an FDA-approved test.35
Considering the rarity of this disease, therapies with tumor- agnostic indications should be considered an attractive option
| Genomic Alteration | Treatment |
|---|---|
| MSI-H or dMMR | Pembrolizumab: FDA-approved |
| TMB-H; ≥ 10 mutations/megabase | Pembrolizumab: FDA-approved |
| NTRK gene fusion | Larotrectinib and entrectinib: approved by EMA and FDA |
| BRAF mutation | Dabrafenib plus trametinib: FDA agnostic approval for tumors harboring BRAF V600E |
dMMR = mismatch repair deficient; EMA: European Medicines Agency; FDA= Food and Drug Administration; MSI-H = Microsatellite instability-high; TMB= tumor mutational burden
for the treatment of advanced or metastatic ACC (Table 4). In 2018, Pembrolizumab received FDA approval as tumor-agnostic therapy for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors after progression to standard treatments. Subsequently, the drug was also approved for solid tumors with tumor mutational burden-high (TMB-H; ≥ 10 mutations/megabase), as determined by an FDA-approved test.41 In USA and Europe, larotrectinib and entrectinib are approved for treating adult and pediatric patients with solid tumors with a neurotrophic receptor tyrosine receptor kinase (NTRK) gene fusion.42 Moreover, the combination of dabrafenib plus trame- tinib recently received granted accelerated approval by the FDA for the treatment of unresectable or metastatic solid tumors harboring BRAF V600E mutation and refractory to conventional therapy.43 NGS testing should be performed when available for the use of agnostic-approved drugs.
Finally, multicenter and international collaboration is essential for trial recruitment and homogenizing ACC care. The Global Society for Rare Genitourinary Tumors (GSRGT) is a society dedicated to education and research for rare tumors, with a very active group focused on the management of adrenal tumors. A website (https://www.adrenalmass.org/) gathers all the evidence available and makes it immediately useful to physicians and patients.44 The European Network for the Study of Adrenal Tumors (ENS@T) and the American-Australasian-Asian Adrenal Alliance (A5) are other consortiums studying this disease, as collaboration to improve outcomes of patients with this rare tumor is critical.
Conclusions
ACC is a rare disease but is associated with a poor prognosis. Treatment recommendations are based on retrospective and small studies with limited systemic therapy options. A multidisciplinary approach is fundamental and genetic evaluation is recommended for all patients. International and multi-center collaboration is essen- tial to improve outcomes. Genomic-driven treatment is a promising strategy and NGS should be performed when available.
Author Contributions
Tiago C. Padua had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
TCP, PS, AN: Conception; Data collection; Interpretation of data.
All Authors: Writing the article; Review & Editing the final version of the manuscript.
Disclosure
Andrea Necchi: Honoraria: Roche, MSD, AstraZeneca, Janssen, Foundation Medicine, Astellas; Consulting or Advisory role: MSD, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, Rainier Therapeu- tics, Bycicle Therapeutics, Basilea Pharmaceutica; Research Funding (Institution): MSD, AstraZeneca, Gilead, Bristol-Myers Squibb; Travel, Accommodations, Expenses: Roche, MSD, AstraZeneca, Janssen; Employment and Stock Ownership (spouse): Bayer: Academic appointments: Vice-president of the Global Society of Rare GU Tumors (GSRGT), ASCO 2022 Annual Meeting Faculty, ESMO 2023 Annual Meeting Planning Committee - GU Kidney and Bladder cancers track, ESMO Faculty - Genitourinary tumors- Non prostate, 2021-2025, Panel member of the ASCO/EAU penile cancer guidelines committee, Board member - EAU Research Foundation (EAU-RF).
Philippe E. Spiess: President of the Global Society of Rare Genitourinary Tumors (non-financially incentivized).
Julie Hallanger-Johnson: consultant for HRA Pharma (mitotane).
All remaining authors state that they have no conflict of interest that might bias this work.
Acknowledgments
Tiago C. Padua is supported by the European Society for Medical Oncology (ESMO) Fellowship.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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