Phillip Koo Hello, my name is Phillip Koo, and welcome to UroToday. One of our goals at UroToday is to bring a global perspective with regard to various topics in GU oncology and prostate cancer. And today, we're very fortunate to have with us Dr. Ray Manneh, who's a GU medical oncologist and the scientific director at the Society of Oncology and Hematology from del Cesar, Columbia. Very fortunate to have Ray with us, who's trained across the world, actually. I believe you spent some time in Spain, as well. So really brings a great global perspective on some of these issues that we're dealing with, especially in prostate cancer. Thank you, Ray, for joining us.

Ray Manneh Kopp: Thank you. Phillip. It is really a real pressure to be here with you, and thanks for the opportunity to be here. Today, I'm going to talk about the novel approaches in the management of high-risk prostate cancer. This is the agenda we are going to follow. We are going to do a brief in, then we are going to talk about the diagnosis criteria we are using right now, the novelties in the diagnosis. After that, we are going to talk about the adjuvant alternatives that we have in this disease. And at the end, the take-home messages.

Prostate cancer is the most common malignancy among men in America. It's the third cause of cancer-related death in our hemisphere. In Western countries, it represents around 15% of localized diagnosed, and around 35 to 40% of prostate cancer deaths are diagnosed as high-risk prostate cancer. In Latin America, we have around a rate of high-risk prostate cancer that is around 30 to 35% in our population. In the first world, it's around 10 to 15%, so we have to improve our detection rate and our screening strategies.

The D'Amico definition stands that a patient with high-risk prostate cancer has at least a cT2c tumor with a Gleason 8 or more, with a PSA above. The NCCN criteria defines high-risk and very-high-risk prostate cancer. For example, high-risk prostate cancer has one of the following. For a patient with cT3a, grade group 4 or 5, and/or a PSA above 20. Very-high-risk prostate cancer must have at least one of the following. cT3b or T4, Gleason pattern 5, two or three high-risk features, or more than four cores with grade group four or five Gleason score.

The news in the diagnosis of high-risk prostate cancer are the development of PSMA radiotracers. We have approved gallium 68 PSMA and DCFPyL. These approvals are based in the PSMA-PreRP trial that used gallium 68. The investigators found that 27% of the patients with intermediate and high-risk prostate cancer had at diagnosis lymph node metastasis. They also showed a sensitivity of 40 to 44% and a specificity of 95 to 97%.

The other important trial that we saw last year was the OSPREY trial that tested this DCFPyl in a similar population showing as similar sensitivity with a high specificity, as well. When we use PET Cts, we are facing new potential scenarios. We may have a patient with high-risk prostate cancer with an N+ positive disease on the PET CT. We also may have patients with limited disease in the bone with a limited number of lesions, but we may also have a bone and lymph node disease with more than five lesions in this patient. It's unusual, but we can see patients with high-risk prostate cancer by conventional imagining with visceral disease in the PET CT. So we are going to see it more that we use, and we will need new trials in order to know what is the best treatment for these patients.

Talking about treatments, adjuvant chemotherapy after radiotherapy. We have several trials with different included populations with different results. One of the most important trials is RTOG 05 that tested docetaxel for six cycles plus ADT, and they saw a benefit in terms of disease-free survival and overall survival. Our group did a meta-analysis with four of the most important trials in this setting, and we saw an over overall survival that was not benefiting patients with docetaxel, but a benefit in terms of disease-free survival. Several trials, different populations. Meta-analysis showing that the outcomes in terms of overall survival are not clear, so the guidelines recommend only for high-risk prostate cancer patients.

The news in systemic treatment intensification for localized prostate cancer. The last news came from ESMO last year. This is the results of another branch of the STAMPEDE platform protocol. Dr. ATAR showed us the results of adjuvant abiraterone tested in this population. Patients had to have node-positive disease, or T3 or T4 tumors, or a PSA more than 40 milligrams, and a Gleason 8, 9, or 10. They also included patients relapsing after a radical prostatectomy or radiotherapy. This was a small size of this whole population.

This is the study design. They compared the standard of care that was ADT for three years plus the radiotherapy and the control. The other arm was standard of care plus abiraterone or abiraterone plus enzalutamide. The results in terms of population, you can see that mean age was 68 years. The median PSA was above 30 ng/ml, and around 40% of the population was N1 by conventional imaging. The results in terms of metastasis-free survival were improved with abiraterone with a hazard ratio of 0.53, and this benefit was translated in an overall survival benefit.

So I think, Phillip, that we have now a new standard of care in the adjuvant setting of high-risk prostate cancer after radical radiotherapy. The take-home messages is that radical prostatectomy and radiotherapy trials were done in the high-risk population guided by conventional imaging. Nowadays, PET CT with N1 or M1 disease doesn't mean that we are not trying to cure this population. We need to maintain the curative intent. We need new trials in the regard to test the metastasis-directed therapy added it to the curative intent. Abiraterone is a new, clear standard of care after radiotherapy in these patients. Thank you, Philip. I'm happy to take some questions.

Phillip Koo: Great. Thank you very much for that really enlightening presentation. So, Ray, that was really thought-provoking, and I love the one take-home message that just because it's PSMA positive that we should give up on curative intent because I agree. We still have a lot to learn, and our intent should be to cure. What advice do you have for urologists and medical oncologists out there treating these patients when they start seeing metastases on PSMA PET and there is no data to help them make the appropriate decisions?

Ray Manneh Kopp: Yeah. I'm going to tell you what are we doing in our group. I think this may guide the decision-making. We take the decision of whether radical prostatectomy or radiotherapy based on conventional imaging. After that, we perform a PSMA PET CT, but the decision to the radical treatment is already discussed with the patient. And when we see the PSMA PET CT, we intensify on top of the curative intent for our patients. Of course, if we see too much disease in the PET CT or visceral metastasis or unusual things, we may change our initial approach. But most of the cases, we stick on the plan and we may add, for example, metastasis-directed therapies to our patients.

Phillip Koo: I love that approach. I love that framework of coming to a decision based on conventional imaging, what you would've done before, and finding ways to intensify but still being open to the idea that maybe, yeah, you'd have to change your decisions severely because of high volume disease or whatnot. So if you think in the future and you think about what type of trial you would like to design in this high-risk space, what are some areas that you would love to see be addressed in future clinical trials?

Ray Manneh Kopp: I think that we should engage patients in clinical trials testing the outcomes of the PSMA PET Cts adding to the new hormonal treatments or the new chemotherapies or new intensification strategies. Around 30 to 35% of high-risk prostate cancer patients relapse. There is lots of deep relapses that mean that the patient is not going to be cured. So we need to improve our treatments, but we also need to improve our knowledge in terms of what does a PSMA PET CT, a negative PSMA PET CT means, or what does lymph node means in the pelvic area or in the retroperitoneal lymph node means. We do not know what does this mean in terms of outcomes, in terms of long-term outcomes for our patients. So I think we need to incorporate this new imagining to the regular trials and follow the patients to see whether their behavior is different or not.

Phillip Koo: Left me shift gears a little. Ray, you have a really broad global perspective on prostate cancer, and especially Latin America having spent time in various Spanish-speaking countries. What do you see as the biggest opportunity with regards to development with regards to prostate cancer in Latin America, and what direction we should be heading?

Ray Manneh Kopp: When the big countries have doubts in our developing countries, we may face difficulties. For example, in terms of the screening, our community doesn't really know how to establish a screening strategy because there are conflicting data. There were conflicting data. And we don't know whether we can apply these results to our population because we have really limited access to urologists, to oncologists, to other specialists. I think that one of the big major steps that we should accomplish is to increase the screening because we are seeing lots of high-risk prostate cancer, lots of metastatic hormone-sensitive prostate cancer. We will need to improve that with a really nice screening procedure.

Phillip Koo: You know, the best cure is to prevent or treat early, so I think that will have a huge impact across the globe. So thank you very much for your time and your insight today, and we're really honored to have you with us.

Ray Manneh Kopp: Thank you, Phillip. It's a real pleasure.