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EAU21: Virtual meeting but crucial findings!

By Dr. Pradere and Dr. Xylinas

This year again, we had to virtually assist at our favourite annual congress. In front of the screen or behind the scenes, this new edition of the Annual EAU Congress met all our expectations.  Lively debates, studies presentation, surgical videos, etc.… From translational research to the operating room to systemic treatments, everything was done to ensure a memorable congress despite the lack of gathering with our friends and colleagues.

We encourage you to go to the EAU21 Virtual Platform to watch the tremendous debates and state-of-the-art lectures that are available on demand.  This is the way to get the best updates on every timely topic.

Besides the exciting plenary sessions and rapid-fire debates, many great studies were presented. Below you can find a short summary of a selection of them:

Neoadjuvant Pembrolizumab in UTUC: disappointing results but the future might be bright

Dr. Andrea Necchi presented the first study assessing CPI in localised UTUC. Indeed, the PURE 02 study aimed to assess the feasibility of neoadjuvant pembrolizumab before radical nephroureterectomy (RNU). The primary endpoints were designed to test the reliability of the EAU Guidelines high-risk UTUC criteria and to assess the clinical activity (based on ypT0N0 rates) and the safety of pembro in the neoadjuvant setting.

Ten patients were enrolled; nine completed the pembrolizumab administration and one died from severe adverse events. Seven patients underwent RNU: only one (14.3%) achieved a ypT1N0 response; the others did not respond. Regarding the molecular and imaging assessment, 3/6 baseline ctDNA assays failed due to the small amount of DNA, and mpMRI was not able to discriminate any response.

After these preliminary results of the use of pembrolizumab in the neoadjuvant setting, it remains debatable whether there is a potential effect of single CPI therapy for UTUC patients. Nevertheless, the future will be exciting with the improvement of patient selection, especially with molecular biomarkers that will allow for a refined therapy selection.

NIMBC: a bunch of early results but good things come to those who wait

 “The effect of a neoadjuvant instillation of chemotherapy in the prevention of recurrences of non-muscle invasive bladder cancer. Preliminary results of the PRECAVE prospective, controlled, randomised clinical trial” was one of the abstracts presented at EAU21. Patients with NMIBC were randomised into immediate neoadjuvant instillation of chemotherapy 15 minutes before TURBT and TURBT only. 180 patients were randomised and 116 met the inclusion criteria. After a median follow-up of 17 months, there were 23 recurrences (immediate neoadjuvant instillation of chemotherapy group n=12 – 19.7%; Control n=11 – 20%) with no difference in recurrence rate by group (p = 0.88). There was no difference in terms of complications and no systemic AE was reported. Longer follow-up is now awaited before drawing any conclusion.

The MITOBCG study was presented by Dr. Cosimo De Nunzio. This study is an open-label phase-4 study which evaluates the safety of sequential MMC and BCG therapy compared to BCG monotherapy in patients with HRNMIBC. The experimental arm received BCG with an additional 40mg MMC the day before BCG instillation. So far, there was no significant difference between the two groups in terms of QOL and AE. Oncological outcomes are still expected to decide if this treatment option might be used in the future.

A Japanese randomised clinical trial of intravesical MMC plus cytarabine (Ara-C) versus mitomycin C for NMIBC patients was presented. Indeed, it has been shown that urine pH is closely associated with the anti-cancer effects of MMC, and consequently it needed alkalisation to improve the efficacy of the chemotherapy. Moreover, Ara-C is used as an intravesical therapy, and interestingly the pH of the Ara-C solution is reported around 8.0 to 9.3. Therefore, the authors assessed the benefits of the combination of Ara-C to increase the anti-cancer effects of MMC through urine alkalisation. 200 patients were enrolled with eventually 79 patients in the MMC group and 86 patients in the MMC+Ara-C group. Recurrence-free survival in the MMC + Ara-C group was significantly longer (p=0.018) compared to those in the MMC group. Recurrence-free survival was also significant in patients with intermediate-risk disease (p=0.008) but not in high-risk patients (p=0.315). Urine PH in the mitomycin C + Ara-C group was higher compared to the mitomycin C group. Regarding AE, there was no difference between the groups.

A post-hoc analysis from a previously published phase-III trial of nadofaragene firadenovec in BCG-unresponsive NMIBC was presented. Previously, the study had met its primary endpoint with 53.4% of the patients with CIS ±Ta/T1 achieving a complete response, with 43.6% of them remaining free of high-grade recurrence at 15 months. Subgroup analyses were based on the efficacy population in the following subgroups: age group (<70 or ≥70 years), sex, disease status at baseline (BCG-refractory or BCG-relapsed), prior lines of therapy (0 or ≥1), prior non-BCG regimens (≤3 or >3), and prior courses of BCG (≤3 or >3). There were no significant differences in response rates between the subgroups in both cohorts, except between patients in the CIS +/- Ta/T1 cohort, who had received <=3 vs >3 prior courses of BCG at baseline. Multivariable analyses confirmed no significant differences in response rates between all subgroups. These results demonstrate the efficacy of nadofaragene firadenovec regardless of patient characteristics or prior treatment history. Moreover, some exploratory analyses were performed to assess anti-adenovirus antibody response correlating with efficacy. For this analysis, blood samples for anti-adenoviral antibody level assessments were collected between 24 hours and 1 hour pre-dose on day 1 and at month 3, 6, 9, and 12 – or at a withdrawal-from-treatment study visit. The researchers found that significant anti-adenovirus antibody response is associated with treatment response and that this may be used to identify responders. Indeed, in the CIS ± Ta/T1 cohort, significantly more patients had a positive post-baseline immunogenic response (43 vs 8; p= 0.0033). In the high-grade Ta/T1 cohort, too, more patients had a positive post-baseline immunogenic response (30 vs 4; p= 0.0003)

Advanced/metastatic urothelial carcinoma: are ctDNA and the other biomarkers ready for primetime?

Since a couple of years, new stars are shining on the stage across the different onco-urological congresses. Biomarkers are here and assessed in many different studies. At EAU21, two exploratory studies from famous RCT have come to our attention regarding biomarkers in mUC.

Exploratory analyses from the IMvigor010 study were presented, specifically an analysis of ctDNA-tested patients and their correlation to outcomes. One of the potential future roles of ctDNA would be to determine risk and need for treatment intensification, especially perioperative systemic therapy. In this analysis, the authors hypothesised that plasma ctDNA positivity is associated with a worse prognosis, atezolizumab provides disease-free survival or overall survival benefit in these patients, and ctDNA clearance occurs at a higher rate with adjuvant therapy. Among the IMvigor010 cohort, 281 patients were in the observation arm (98 ctDNA-positive) and 300 in the atezo arm (116 ctDNA-positive).

ctDNA status was shown to have a prognostic value: ctDNA-positive patients had worse DFS and OS. Moreover, ctDNA-positive patients who had received adjuvant atezo did better than patients who were on BSC/surveillance. The authors also found that patients who were TMB-high and showed ctDNA(+) had better DFS and OS. Finally, changes in ctDNA status were also associated with treatment arm and survival. Patients treated with atezo were more likely to get rid of ctDNA and this clearance was associated with improved DFS and OS. These results are highly promising and most likely convinced even the person most sceptical of the major role ctDNA analysis might play in the near future.

We are now looking forward to the IMvigor011 study, which aims to prospectively validate this concept for a ctDNA-based treatment strategy.

Another exploratory analysis of the DANUBE trial, with a focus on the outcomes of durvalumab with or without tremelimumab stratified by cisplatin-eligibility and PD-L1 biomarker status in metastatic urothelial carcinomas, was presented by Prof. Tom Powles. Of note, the DANUBE trial is an RCT comparing first-line durvalumab alone to durvalumab + tremelimumab to standard-of-care chemotherapy in patients with locally advanced/metastatic UC. The study was not able to reach its primary endpoint (no significant benefit in OS in Durva or Durva/Treme compared to SOC). In the exploratory analysis, the authors showed that Carbo/gem patients have outcomes which appeared longer than historical controls, with response rates and PFS in line with cisplatin-based chemotherapy. Moreover, Durvalumab showed activity in the cis-ineligible, PD-L1-high population, in line with results of other ICIs in this population, but this was not statistically significant. The authors confirmed that tremelimumab appeared to improve the activity of Durva in a combination.

More results from ongoing trials such as the Phase-3 NILE and VOLGA will further explore the Durva/Treme combination in mUC.

We hope that you enjoyed watching EAU21 as much as we enjoyed covering it – although we are looking forward to meeting you in person soon! Until then, don’t hesitate to watch all our interviews on our dedicated UroOnco platform!