Darren Poon: So good morning, friends and colleagues. I'm Darren Poon from Hong Kong. Thank you APCCC, for the very kind invitation. It would be my great pleasure to share with you my humble opinion on the management for the clinical N1 positive prostate cancer.

So these are my disclosures.

In the AJCC 8th editions, patients with regional nodal metastasis, that are located below the aortic bifurcation, will categorize at stage 4A disease. Historically, the presence of perinodal metastasis was commonly regarded as incurable, and were managed with ADT alone. And all along, no specific randomized trial for this particular subgroup, and the data mostly derived from retrospective series.

And the controversy around this subgroup of patient is whether this is an intermediary stage, between high-risk locally advanced disease, and low volume mHSPC. And apart from ADT, various evidence has suggested that both local treatment, as well as systemic therapy, are essential in further enhancing the clinical outcome for patients with N1 disease.

For local treatment, for example, in the analysis of the control arm of the STAMPEDE study, the failure free survival is significantly better with the additions of radiotherapy in high-risk M0 and N1 disease. And in the propensity score, matching analysis of the NCDB data, the oncological outcome is also better with the additions of radiotherapy to the prostate in N1 disease.

While radiotherapy has been the commonly used local treatment, in this systematic review, published in European Urology Oncology, there's a consistent survival benefit with any form of local treatments. However, these evidence were mostly retrospective, and that there is limitations, as listed in this table.

While radiotherapy has been considered as an essential part in treating high-risk M0 and N1 disease, the optimal dose and fractionations remains uncertain. Various fractionation has been used for the prostate primary. Say for example, from conventional fractionation to SBRT. And further dose escalations to the prostate with brachytherapy, or intraprostatic lesion boost, as supported by the ASCENDE-RT and FLAME study, may further improve the clinical outcome.

And based on the POP-RT study, whole-pelvic radiation, in addition to the prostate primary radiotherapy, could reduce the risk of biochemical recurrence and distant metastasis in high-risk prostate cancer. And nowadays, with the MRI guided radiotherapy, we could perform realtime adaptive planning for the nodal boost, based on the daily MRI images. So, for example, like in this case, you can appreciate the perfect nook as substantial volume changes over time. I think these contemporary radiotherapy may further substantiate a trim in outcome for the high-risk M0 and N1 disease.

On the other hand, nowadays, the ADT plus approach has already become the standard of care, in both low and high volume mHSPC. As N1 disease could be considered as a stage before the low volume mHSPC, it is interesting to see the role of combination chemo, or AR agents, in this subgroup.

Despite there's a significant survival benefit, failure-free survival benefit, with combination docetaxel in high-risk M0 disease, based on the meta-analysis that includes STAMPEDE, GETUG-AFU GC-0521 study, the overall survival benefits of combination docetaxol in this subgroup remains undetermined.

And on the other hand, the outcome of combination abi by the STAMPEDE group for the high-risk M0 and N1 disease, has been reported together with the metastatic disease, by Nick James five years ago. Although the benefit is very clear with the metastatic disease, however, in this primary analysis, the M0 group had sufficient events for the certainty of the overall survival benefit with the combinations abiraterone.

And until recently, the role of combinations abiraterone and ADT and radiotherapy in non-metastatic prostate cancer, has been assessed by the STAMPEDE group, and is recently presented in ESMO, and published in Lancet, by Professor Akhtar and his group. And in this analysis, they split M0 patients from the M1 patients. And this analysis was powered for the primary endpoint of metastasis-free survival. And the meta-analysis method was used to put data from two trials that randomly assigned patients to three years of ADT with or without two years of abiraterone, or abiraterone with enzalutamide.

And this analysis include patients with node positive or high-risk, node negative disease. And that definitions of high-risk disease are those with at least two out of three adverse factors, namely, T3 or T4 disease, Gleason six to 10, or PSA 40 or above. And the same time, the high-risk relapsing patients were eligible as well. And conventional imaging were used to exclude metastasis in this study. And this analysis includes around 1009 of their patients, with a median age of 68. 39% of them have node positive disease. And radiotherapy has been given in around 70% of them, with the median followup time, 72 months.

The metastasis-free survival was improved by about 47%, with the additions of combination abi. And the overall survival was also significantly improved by 40%, with combination abiraterone, with the six year survival improved from 77% to 86%. And the benefits of abiraterone was observed in all subgroups, including both node-negative and node-positive disease. Therefore, based on this STAMPEDE study, the additions of two years of abiraterone to radiotherapy and ADT, should now become the new standard of care for the high-risk M0 and N1 disease.

Apart from abiraterone, other AO agents are being investigated. For example, apalutamide and enzalutamide are being investigated in the ATLAS and ENZARAD trial, respectively, in additions to the radiotherapy. Both studies had completed the patient accrual, and the results are eagerly awaited. And in the current NRG GU009 study, patients with high Decipher score and node-positive disease, they will be randomized to standard of care, or intensification approach, with the additions of two years of combination apalutamide and abiraterone. And you would be very interesting to see if such AL combos could further substantiate a trim in outcome in node-positive disease and higher genomic risk disease.

While the combination of systemic therapy with radiotherapy has shown promising, clinical outcome in high-risk M0 and M1 disease as you have seen, the role of perioperative systemic treatments remains undetermined.

In a CALGB study, neoadjuvant chemo, hormonal therapy was compared to the radical prostatectomy alone in high-risk localized disease. Although, the secondary endpoint, such as overall survival, was improved with preoperative docetaxel, the primary endpoint of biochemical progression-free survival was not met.

On the other hand, given the very encouraging down staging event with preoperative AR agents in previous Phase II studies, the preoperative apalutamide was being compared to radical prostatectomy alone in this ongoing Phase III PROTEUS studies. However, the role of perioperative systemic therapy remains investigational, at this moment, I think we should only be contemplated in the context of clinical studies.

In the past, around five to 10% of patients with newly diagnosed prostate cancer. We have newly, we have synchronous nodal metastasis, based on the conventional imaging. I think this proportion of patients is expect to be increased with novel images, such as PSMA PET. In the landmark proPSMA PET study, around 20% of high-risk localized prostate cancer, were found to have perinodal metastasis, based on the PSMA PET, which is much higher compared to conventional imaging. However, very important questions regarding the use of PET imaging, is whether such high detection rate would translate into better clinical outcome.

Nowadays, there are a few ongoing studies in investigating the applications of PSMA PET in the primary definitive treatment for prostate cancer. In this Canadian PATRON study, patients will be treated with a personalized approach according to the PET imaging. For example, for patients who are found to have pelvic nodal metastasis on PSMA PET, nodal boost with radiotherapy or the resection of the involved nodes, will be contemplated. I think these studies will help, definitely help, to validate the value of novel imaging in treating high-risk M0, as well as N1 disease.

 In conclusion, despite N1 disease is categorized as stage 4A disease, it is believed that it is in the middle stage between high-risk M0 and low volume mHSPC.

While radiotherapy is considered as the mainstay of treatment as for the metastatic disease, local treatment, especially with radiotherapy or surgery, appears to improve oncological outcome, in addition to ADT. Contemporary radiotherapy would further substantiate the therapeutic window, by delivering a more precise and safe radiation to both prostate primary and the pelvic lymph node.

Based on the STAMPEDE study, the additions of two years of abiraterone to ADT and radiotherapy, confer a clinically meaningful significant survival benefit. And it should be considered as the standard of care nowadays, for high-risk M0 and N1 disease.

Other AR agents are also being investigated in the combinations with radiotherapy or surgery, but combination chemotherapy should not be routinely offered for the high-risk M0 and N1 disease, as there is no overall survival benefits.

The high detection rate with the PSMA PET scan, as compared to conventional imaging, we need to more N1 diseases in the coming future. And we are looking forward to the results of the PET guided treatment approach, and see if this could translate into better clinical outcome.

Finally, I would like to thank you once again, APCCC, for providing me the chance in participating this meeting virtually. And since this lecture is pre-recording with stringent time limit, I don't have the chance to elicit the famous APCCC cowbell. I hope I could join the next APCCC in person, and I wish you all the best with good health. Thank you very much for your kind attention.