Sergey Dyshlovoy, Hamburg, D
Introduction: Development of aggressive variants of metastatic castration-resistant prostate cancer (AVPC) is a major challenge in the course therapy. However, the underlying mechanism of aggressive transdifferentation is not completely understood and appropriate tumor models are missing. Here, we investigated the consequences of long-term taxane exposure on well characterized hormone independent, BRCA2 mutated 22Rv1 cells expressing the AR-V7.
Methods: 22Rv1 cells were treated with continues 10-months treatment of stepwise increased taxane concentrations. Individual clones were picked and cultured in media containing either Doce (12.5 nM) or Caba (2 nM or 5 nM). Age-matched parental (Ag) cells were maintained in culture without treatment. Further characterization was carried out using proliferation, migration, metabolic, and colony formation assays as well as proteomics and RNAseq analyses at defined time points.
Results: In total, three 22Rv1-DR clones (50-100-fold resistance to Doce) and three 22Rv1-CR clones (80-150-fold resistance to Caba) were chosen for further investigations. Both, 22Rv1-DR and 22Rv1-CR cells exhibited cross-resistance to Caba and Doce, correspondently, however, being much more pronounced in the latter. Cell morphology changed upon long-term taxane exposure with a shift in favor of the nuclear-plasma ratio and accompanied by a loss of adherent properties. In addition, lower proliferation, metabolic rates and colony-forming ability were observed when compared to control 22Rv1 cells, whereas migration activity of some clones was increased. Further proteomics and RNAseq analyses identified 78 and 52 genes commonly affected in 22Rv1-DR and 22Rv1-CR clones, correspondently. Expression of 14 genes was altered in both the 22Rv1-DR and 22Rv1-CR clones in comparison to non- resistant cells. Among these genes, expression of ABCB1 (P-gp, multidrug resistance protein 1) was upregulated. Further bioinformatical analysis suggested neuroendocrine transdifferentation to be stimulated in PCa under continuous treatment with Doce or Caba.
Conclusions: Long-term taxane exposure resulted in the expected drug resistance caused by well- known chemoresistance mediating genes including ABCB1 (P-gp). However, signs of neuroendocrine transdifferentation were detected in some clones suggesting alternative escape mechanisms by transdifferentation. These clones are currently under investigation in order to identify key events in the development of AVPC.
V586 Vergleich der Wirksamkeit und Sicherheit einer Hochdosischemotherapie als 1. Salvage-Therapie gegenüber dem Einsatz als 2. oder spätere Salvage-Therapie bei Patienten mit rezidiviertem oder refraktärem Keimzelltumor - eine retrospektive Single-Center Analyse
Nils Wolfgang Engel, Hamburg, D
Introduction: About 30% of germ cell tumor (GCT) patients with initial metastatic disease relapse despite cisplatin-based first-line therapy. For patients, who relapse following conventional salvage therapy, high-dose chemotherapy (HDCX) as 2nd or subsequent salvage treatment can be considered, but data on efficacy and safety of HDCX in a late-line scenario is sparse. This study aimed to compare efficacy and safety of HDCX in 2nd or later-line salvage vs. 1st salvage treatment.
Results: A retrospective review of 479 GCT patients' medical records identified 72 evaluable patients receiving salvage HDCX for relapsed or refractory GCT between 2007 and 2020 with a median follow-up of 22.1 months from time of first recurrence. Of these, 57 patients (79.2%) received HDCX as 1st salvage and 15 patients (20.8%) underwent HDCX as 2nd or later-line salvage treatment. Patient characteristics between these groups were similar regarding median age at diagnosis (32 vs. 27 years, p=0.23) and primary histology (seminoma/non seminoma: 14.3/85.7% vs. 20/80%, p=0.689). Most of the patients (81.9%) were able to receive 3 HDCX cycles with no detectable difference between groups (p=0.467). Compared to 1st salvage HDCX patients, 2ndor later salvage HDCX patients tended to have a more favorable risk profile in our cohort with respect to IGCCCG risk category (p=0.047) and a lower incidence of brain, bone and liver metastasis at 1st salvage (p=0.019).
The median OS from time of first recurrence was not significantly different between the groups of 1st salvage HDCX and 2nd or later salvage HDCX patients (p=0.387), associated with a 2-year-OS-rate of 80.4% vs. 75.0% and a 5-year-OS rate of 61.9%% vs. 45.0%, respectively. The RR after HDCX between groups was comparable (49.1 vs. 53.3%, p=1).
The mean rate (± SD) of selected G3 or any G4/G5 adverse events per HDCX cycle between groups was similar between 1st salvage HDCX vs. 2nd or later salvage HDCX (0.82±0.44 vs. 1.04±0.60 events/cycle; p=0.145).
Conclusion: HDCX was safe and effective in our cohort irrespective of the salvage line it was applied in and should be considered for all relapsed GCT patients, even when used in later salvage lines.
V5 Finale Analyse der TITAN: Eine Phase 3 Studie mit Apalutamid (APA) vs Placebo (PBO) bei Patienten mit metastasiertem kastrations-sensitiven Prostatakarzinom (mCSPC), die eine Androgen-Deprivations Therapie (ADT) erhalten.
Axel Stuart Merseburger, Lübeck, D
Background: TITAN evaluated APA or PBO added to ADT in pts with mCSPC. Pts with high- and low- volume disease, prior docetaxel, prior treatment for localized disease, and prior ADT (≤ 6 mos) were eligible. At the first interim analysis, with 22.7 mos median follow-up, APA significantly improved dual primary end points of overall survival (OS) (hazard ratio [HR] 0.67) and radiographic progression-free survival (rPFS) (HR 0.48) compared with PBO (Chi et al. NEJM. 2019). At that time, OS analysis was first planned interim while rPFS was final. TITAN was unblinded, allowing pts without progression who were still receiving PBO to cross over to APA. Herein, we report the final analysis of efficacy and safety results from TITAN.
Methods: 1052 mCSPC pts were randomized 1:1 to receive APA (240 mg QD) or PBO plus ADT. Time-to- event end points were analyzed by Kaplan-Meier method and Cox proportional hazards model. A preplanned sensitivity analysis for OS, accounting for crossover using inverse probability censoring weighted (IPCW) log-rank test, was conducted. No formal statistical retesting was performed; nominal p values were reported without multiplicity adjustment. Change from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score was assessed using a mixed-effect repeated-measures model.
Results: With 44 mos median follow-up, 405 OS events had occurred. After unblinding, 208 PBO pts (39.5%) crossed over to APA. Median treatment duration was 39.3 mos for the APA group, 20.2 mos for the entire PBO group, and 15.4 mos for the PBO→APA crossover group. OS was superior in the APA group compared with the PBO group despite crossover (Table). 48-mo survival rates were 65% (APA) vs 52% (PBO). Other end points also favored APA vs PBO (Table). Health-related quality of life (HRQoL), per total FACT-P, was maintained in the APA group through the study and was not different from the PBO group. Safety was consistent with previous reports.
Conclusions: With close to 4 yrs of follow-up, the final analysis of TITAN demonstrated that in a broad population of pts with mCSPC, APA plus ADT provides an improvement in OS with a 35% reduction in risk of death, which increased to 48% reduction after adjusting for pts who crossed over from PBO to APA. In addition, there was consistent benefit with APA in other end points, including delaying castration resistance, and HRQoL continued to be maintained with an acceptable safety profile.
V482 Eine laufende, randomisierte Phase-II Studie zum Vergleich der Wirksamkeit von Nivolumab plus Ipilimumab versus Standardtherapie bei Patienten mit bisher unbehandeltem und fortgeschrittenem, nicht-klarzelligen Nierenzellkarzinom (SUNIFORECAST)
Marit Ahrens, Frankfurt, D
The heterogenous group of non-clear cell renal cell carcinomas (nccRCC) account for approximately 25% of all RCC patients (pts.). Since most clinical trials only or predominantly include clear-cell RCC (ccRCC) histology, data on treatment algorithms for nccRCC are still limited. Different combination therapies with immune checkpoint inhibitors (IO, Avelumab, Nivolumab or Pembrolizumab) and tyrosine kinase inhibitors (TKI) (Axitinib or Cabozantinib) have recently been approved for treatment in RCC independent of the International Metastatic RCC Database Consortium (IMDC) risk group. Moreover, Nivolumab and Ipilimumab (IO/IO) has been approved for treatment in intermediate and high risk pts. showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) compared to Sunitinib. Additionally, retrospective analysis and smaller trials in nccRCC pts. have shown promising results for IO-based therapies in this subentity.
SUNNIFORECAST is an ongoing, randomized phase-II multicenter European trial including adults with advanced or metastatic nccRCC without prior systemic therapy. Available tumor tissue, Karnofsky >70% and measurable disease per RECIST 1.1 are other key inclusion criteria. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ~306 pts. stratified for papillary or non- papillary non-clear cell histology and by the IMDC risk score. Pts. will be randomized 1:1 to either i) Nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by Nivolumab fixed dose 240mg IV every 2 weeks or fixed dose 480mg IV every 4 weeks or ii) Standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 237 patients (148 pts with papillary, 83 pts with non-papillary histology) have been enrolled until now.
Clinical trial identification NCT03075423
V597 Symptomatisches versus asymptomatisches Urothelkarzinom in Deutschland: 32-Monatsdaten der nicht-interventionellen, prospektiven VERSUS-Studie von d-uo
Rolf Eichenauer, Hamburg, D
Introduction: In May 2018, the German Uro-Oncologists (Deutsche Uro-Onkologen, d-uo) opened their prospective VERSUS study (VERSorgUngsStudie, VERSUS) for the documentation of outpatient diagnosis and treatment of urological tumors. This analysis addressed the question whether age and tumor stage at diagnosis differed between symptomatic vs. asymptomatic urothelial carcinoma (UC) cases.
Methods: VERSUS is a nation-wide non-interventional, prospective, multicentric study for the documentation and evaluation of outpatient diagnosis, treatment and follow-up of urological tumors using descriptive statistics. In this analysis we evaluated patients with first diagnosis of UC. In the d-uo database, the cause of first diagnosis (e.g. symptomatic) can be documented.
Results: Until December 2020, 7,469 patients with first diagnosis of a UC were documented. Out of these, 1,825 patients (24.4%) had UC. 77.7% were men and 22.3% were women, median age was 75.7 years (men 75.8 years and women 75.1 years). In 1004 cases (55%), UC was diagnosed because of symptoms vs. 821 cases (45%) without symptoms. Distribution of stages in symptomatic vs. asymptomatic UC cases is shown in table 1.
Conclusions: Patients with symptomatic UC do not differ with regard to age from those with asymptomatic UC at diagnosis. However, percentage of tumor stage UICC 0 was lower and stage UICC IV was higher in patients with symptomatic compared to those with asymptomatic UC. The VERSUS study continues to collect epidemiologic and clinical data of patients with UC.