Neha Vapiwala: And I'd like to invite for our final talk of the session, Dr. Derya Tilki, a urologist from Hamburg, who will speak to us about the management of pathologic node-positive disease.

Derya Tilki: Thank you very much.

Aurelius Omlin: And briefly, I see a lot of questions on Twitter. So, if you, because we've got now, what, 25 screens here, so if you could put your question in the APCC application, that would be easier for us. Thank you.

Silke Gillessen: And there's also microphones in the room. So afterwards, when we have the question and answer, you can also use these. Thanks, Derya.

Derya Tilki: Thank you. And thank you to Silke and Aurelius for inviting me to speak about the management of pN1 disease. I have disease disclosures. I will talk about trends in prostate cancer, stage migration, the natural history of pN1 disease, management options in pN1 disease, and current guidelines.

We showed last year that rates of patients with positive lymph nodes at radical prostatectomy increased from 3.7% to 10.5% from 2000 to 2012, compared to 2013 to 2020. This is a study by Zareba and colleagues using the national cancer database, looking at the distribution of post-RP management strategies for pN1 disease. And as you see on the left, observation and ADT alone are mostly used. Men with higher-grade tumors were more likely to be treated with ADT alone than observation, radiotherapy alone, or combination therapy. Men with the highest stage tumors were more likely to receive any treatment than undergo observation, and men with a higher positive lymph node count were more likely to receive ADT alone.

With regards to ADT alone, lymph node metastases at the time of radical prostatectomy have traditionally been thought to be a manifestation of widely disseminated disease and consequently poor prognosis. This paradigm was the basis for the randomized Messing trial, which showed higher overall survival among men who received immediate as opposed to delayed ADT. However, recent retrospective studies have shown the heterogeneity of pN1 disease, where not all node-positive patients may be affected by systemic disease. This suggests that immediate ADT represents overtreatment in a lot of men and that further treatment must be individualized based on risk factors.

In this study, we looked at 209 pN1 patients with one or two histologically proven positive lymph nodes without adjuvant treatment, and what we saw is that a substantial subset of patients here, 27%, remain free of biochemical recurrence during follow-up. This is another study by Touijer and colleagues from MSKCC, who also looked at the natural history of pathological lymph node-positive disease and have shown similar numbers. 28% of the pN1 patients in this study remained free from biochemical recurrence at 10 years. For patients with recurrence, most recurrences occurred within the first five years after surgery. Higher pathological Gleason score and three or more positive lymph nodes were significantly associated with increased risk of biochemical recurrence and metastasis, and the 10-year probability of freedom from distant metastasis was 65%.

Multiple multicenter studies looked at the question of adjuvant radiation as an additional benefit to ADT in pN1 disease. On the left, you see a study by Briganti and colleagues who did show that adjuvant radiation plus ADT did lead to better cancer-specific survival compared to adjuvant ADT alone in a propensity score-matched analysis. Similar data were shown again by Touijer and colleagues from MSKCC, who also showed that higher-risk patients benefited more from adjuvant radiotherapy.

Given the worse prognosis with an increasing number of positive lymph nodes, whether the association of a reduction in mortality risk applies irrespective of the number of positive lymph nodes when using adjuvant radiotherapy was explored. After adjusting for the time-dependent use and duration of ADT, we looked here at more than 1,600 patients with positive lymph nodes. At radical prostatectomy, adjuvant radiotherapy use was associated with a significant reduction in all-cause mortality risk compared with early salvage radiation therapy. The magnitude of this reduction increased by 8% with each additional positive lymph node. Men with four or more lymph nodes appeared to benefit the most from the use of adjuvant radiotherapy.

There's no randomized data on the question of whether adjuvant radiotherapy should be used with or without ADT in pN1 disease so far, but there are differing data from retrospective studies. For example, on the left side, a study by Bravi and colleagues who used a single-center experience from San Raffaele in Italy, and did not show any difference in overall survival when comparing radiotherapy to radiotherapy plus ADT. In contrast, on the right side is a study by Wong and colleagues from the National Cancer Database, who did show a difference in overall survival, better overall survival for patients with radiation plus ADT compared to radiation alone.

We may get some insight on this question from the RADICALS-HD study on hormone duration. The study randomized patients to radiotherapy alone, radiotherapy plus six months of hormone therapy, or radiotherapy plus two years of hormone therapy, and we will hear about the pN1 subset probably at the end of this year.

Ahlgren and colleagues looked at chemotherapy in high-risk patients. This is the SPCG-12 study that randomized 459 patients, including 12% pN1 patients after prostatectomy, to six cycles of docetaxel or surveillance. Median follow-up was 57 months; no improvement in biochemical recurrence-free survival, which was defined as rising PSA above 0.5, was demonstrated. The lack of combination of docetaxel to ADT in this trial and the inclusion of patients not classically considered as very high risk for relapse may explain these negative findings.

While we just heard about data on new hormonal agents in the cN1 setting, we don't have data on that yet for the pN1 setting. There's the DASL-HICAP trial and the 1801, which is currently recruiting a randomized international trial of adding darolutamide to ADT and definitive or salvage radiation in very high-risk prostate cancer, and this study will include a stratification on clinical or pathological pelvic lymph node involvement.

Furthermore, in this setting, there's the NRG-GU008 Innovate study. What's unique about this study is it is focusing only on pN1 disease, pathologically node-positive prostate cancer patients at the time of radical prostatectomy, and currently having a detectable PSA, are randomized to radiotherapy plus ADT for two years versus radiotherapy plus ADT plus apalutamide for two years.

I would like to summarize using this systematic review on the management of pN1 patients, which we performed within the EAU Prostate Cancer Working Group. It includes 26 studies with more than 12,500 men. Ten-year biochemical recurrence-free survival ranged from 28% to 56%, and cancer-specific survival from 72% to 98%. While the majority of men with pN1 disease experience biochemical recurrence after surgery, long-term disease-free survival has been reported in selected patients. We saw that the use of adjuvant radiotherapy with or without ADT was shown to improve survival in men with locally advanced disease and a higher number of positive lymph nodes. Risk stratification, according to pathological Gleason score, the number of positive nodes, and pathological stage, is key for the selection of the optimal postoperative therapy. The uncertainty regarding the optimal management of pN1 disease is reflected in the guidelines, as seen here for the EAU guidelines, which list observation, adjuvant ADT, and radiotherapy plus ADT as management options with a strength rating of weak. Thank you.