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Alicia Morgans: Hi, I am so excited to be here today with Professor Yang, who is joining me today from the Cancer Hospital of Peking University, and I'm very excited to talk about cases with you related to the ARASENS data. Thank you so much for being here with me today, Professor.

Yong YANG: I'm honored to be here to discuss the case with you.

Alicia Morgans: Wonderful. Before we get into the cases, I would love to be able to ask you some questions about prostate cancer care and prostate cancer statistics in China. Is that okay?

Yong YANG:  Okay, no problem.

Alicia Morgans: Wonderful. I'd love to hear, can you share, what is the incidence rate of prostate cancer in China, and how many of those patients actually have metastatic hormone sensitive prostate cancer?

Yong YANG:  Okay. I'd love to answer the questions. According to the data issued by the Beijing government in 2021 [error in speaking], the incidence of prostate cancer is about 12 per 10,000 population. It doesn't look so high as compared to data from the USA, but unfortunately, the five-year observed survival rate is only about 66.5%. I would say it's much lower as compared to the data from the USA. Many reasons can explain it, and cancer explains the low survival rate of the disease in China. But one reason is the late diagnosis of prostate cancer. Only about, more about 60% of patients with prostate cancer, they are with metastasis at the initial diagnosis.

Alicia Morgans: Wow. That's unfortunate and really striking information, I think. As you said, when we think about comparing that to the United States data that I'm more familiar with, so really important to know, especially as we're thinking about treatments for the metastatic state.
When you are treating patients in China with metastatic prostate cancer, are those patients usually being treated in the department of urology, or are those patients treated by oncologists? How does that work in China?

Yong YANG: But in China, in almost all cities, the first consultation department for prostate cancer is urology. Usually, urologists would evaluate the patient's PSA level, arrange for prostate biopsy, and staging imaging or examinations. But finally, urologists could determine the treatment plan, with patients or family members, to choose radical prostatectomy, radical radiotherapy, or radical medicines. But for patients with metastatic disease, initial treatment would be given by a urologist. But if chemotherapy is necessary in initial treatment, that would be a problem here. Many urologic departments in China could not allow to do the chemotherapy for their patients. Only oncologists could do the job. It might be a reason that urologists in China prefer to give their patients with ADT or ADT plus androgen. It is an easy way to get the job done in urologic departments, but it's not a better way, as we know now.

Alicia Morgans: I think that's probably pretty consistent around the world, that in most countries, urologists don't have access to doing the chemotherapy themselves. So that makes a lot of sense. And of course, the doctor who sees the patient first, wants to try to treat that patient in the way that he or she can. What are the general treatment principles for metastatic hormone sensitive disease in China? And I wonder, are those evolving and changing maybe too?

Yong YANG: Actually, we have almost all medicines for ADT, such as leuprorelin, goserelin, et cetera. And surgical castration also remains for a few patients in poor financial condition here. We also have most medicines for NHT, including abiraterone, enzalutamide, apalutamide, darolutamide, et cetera. And usually, we should follow the guidelines of EAU, AUA, and NCCN.

We can get these international guidelines easily from the web or internet. But we also have our own guidelines for prostate cancer. The guideline of China would consider the actual situation of the country. As you might know, in China, different cities, even different hospitals, have different resources of the medicine I mentioned above. Not even the resource of radiotherapy. Every city in China has its own reimbursement list, but things are getting better recently.

Alicia Morgans: That is wonderful to hear, and also very consistent with what we see with differences in other parts of the world as well. And I wonder, since you are a PI of ARASENS in China, could you share your experience with ARASENS in China through some cases?

Yong YANG: Okay, I'd love to. I will start a presentation of a special case from the ARASENS clinical trial at our trial site. It's a case with prostate cancer. He was 54 years old when he first visited us with the main complaint of hematuria and elevated PSA levels, about 40 nanograms per mL, in late 2017. Also has intermittent dysuria from time to time. At the initial evaluation, an MRI of the prostate showed abnormal nodules at the bilateral peripheral zone.

Soon after, we did process his prostate biopsy for him, and the pathological results confirmed the prostate cancer with positive in every biopsy score. Half over eight, Gleason score, half under seven. CT scan showed bilateral enlarged peripheral lymph nodes as suspected metastasis in the liver, no metastasis in the lung. Bone scan confirmed high volume of bone metastasis. Here are some images of the patient. We can see quite large pelvic lymph nodes, and suspect metastasis in the liver. And it's clear in the lung.

As we know, the patient did not have a very high PSA level. Before we start the treatment, we suspect the patient might have some endocrine lesions in the metastasis. So we did the PSMA PET scan for this patient. It showed all the lesions have a very high expression of PSMA, which means, we believe these lesions are sensitive to endocrine treatment.

And routine blood test is normal, and mildly elevated ALT. This means mild liver function damage and elevated glucose, which means that the patient has diabetes mellitus. So that's a brief information of the patient. So to save time, I just go through the following slides about what we thought at that time. Okay?

Before we diagnosed the patient at the end of 2017. Before 2018, we believed only ADT plus docetaxel and ADT plus abiraterone could be proper options for the patient. Because from these two kinds of clinical trials, we know these two combination treatments could be effective for patients with visceral metastases.

It's the CHAARTED clinical trial. From the stratified analysis we can see the patient in CHAARTED can benefit from ADT plus docetaxel with visceral metastases. And it is the same effectiveness in the LATITUDE clinical trial. With visceral metastases, the patient can benefit from these combinations.

It's not the case in the TITAN clinical trial. As we can see with visceral disease, the patient cannot benefit from ADT plus apalutamide. And also, in the ENZAMET clinical trial, just the same. The patient with visceral metastases cannot benefit, in terms of OS, from the ADT plus enzalutamide.

So before we can get the results from ARASENS for our patients, the only options we have to choose are docetaxel plus ADT, or abiraterone plus ADT. So before 2018, actually we don't have data from enzalutamide from ENZAMET and TITAN. So actually at present, we can see only CHAARTED, LATITUDE, and ARASENS. Combinations could be proper for our patient. But before 2018, with the options for us, it is just the CHAARTED combination, and the LATITUDE combinations.

So actually, I have many questions about these clinical trials. If Dr. Morgans, would you like to share your opinions about your experience about these questions? So the question is, what's the difference among these clinical trials? How to choose proper medicines combination for mHSPC at present time? Would you like to share your experience about that?

Alicia Morgans: I would love to share my experience, and so appreciate this very complex case.
I think that certainly, as you point out in those subgroup analyses, it looks like things like chemotherapy, and perhaps abiraterone, may be most effective when patients have visceral disease. And we know that liver involvement, in particular, is a poor prognostic sign, and we need to be as aggressive in fit patients as we possibly can.

I think that using an ADT chemotherapy combination here, and also trying to use an androgen receptor signaling inhibitor that might limit exposure to steroids in the setting of diabetes, I think is really an optimal way to go, if we're hoping to try to get the best outcome for patients.

When patients have liver function abnormalities, like a mild ALT elevation, I have been able to still use things like docetaxel and darolutamide, or abiraterone in combination. But we do have to watch the liver function tests closely for these patients, and make sure that we keep them safe over time. That close monitoring, I think, is what we would do normally, and is not very far afield from our normal practice. But I would keep a close eye on those liver function tests, and I wonder if you would do the same.

Yong YANG:  Thank you. But what I have been wondering is, if we choose the ARASENS combination, should we consider the patient's age, whether the patient is a proper candidate to choose chemotherapy plus ADT and darolutamide?

Alicia Morgans: Absolutely. This patient seemed to be in his 50s, and I think many patients in their 50s can still have a long and healthy life; compared to patients who might be in their late 70s and 80s, where things like chemotherapy may be more challenging to do. I would say too, that many patients who are in their 50s have fewer other medical comorbidities, and so, it's often easier for us to support these patients through treatment.

All of that being said, there are fit patients who are in their 70s, and even in their 80s, who can still tolerate chemotherapy in this first-line setting. And since they are, at that time, still younger, and probably healthier than they may be in a few years when the cancer progresses, I do, in those cases for fit patients, try to give them the option of chemotherapy earlier. Because I know it will be chemotherapy now, or chemotherapy in the future when the cancer becomes resistant. And so, really trying to balance all of those factors is important. But, great point.

Yong YANG:  Thank you for your experience. I saw a video 2022 on Uro Today. You discussed a case, an old man, about 88 with mHSPC; you recommendation, the ARASENS combination for the older patient, is quite surprising. So it depends on the patient's status, right?

Alicia Morgans: Absolutely. And I think that it is a special patient who is in his late 80s that can take chemotherapy. But I also think it's important for patients to know that we don't look at the number on the chart, on the paper, and say, "I know before I meet you that you can't do something." I think patients appreciate that we evaluate each one as a whole, and not just that number. But yes, it is a very special patient who is 88 and can get chemotherapy.

Yong YANG: Okay. Let's carry on with the cases. The patient was included in the ARASENS clinical trial in January 2018, and he was lucky to be included in the ADT plus darolutamide and docetaxel group. When we look at the whole process of the treatment, the PSA values remain very low for a very long time, in about four and a half years. It looks like this combination works very well for our patient.

And if we compare the bone scan before the treatment and four years after the treatment, we can see the treatment for four and a half years. The bone scan has almost disappeared, which means the combination is very effective for this patient. And in my view, the triplet combination of ADT plus daro and docetaxel could be the best choice for patients. Especially with a high volume, high risk, which means a high Gleason score, castrate-sensitive metastatic prostate cancer. And also, if a patient has diabetes mellitus, abiraterone should be avoided.

Alicia Morgans: Thank you so much for that wonderful case illustrating these points about visceral disease and the patient with comorbidities. It's so common, and really an important case. I wonder, from your experience, which specific patient groups have you seen have better responses when treated with the ARASENS type regimen?

Yong YANG:  I bet mHSPC patients with more aggressiveness could benefit more when treated with the ARASENS combination. But in terms of a better response, I guess, the less aggressive the prostate cancer the better the response could be.

Alicia Morgans: Yes, I agree. It's interesting that we see this in lots of our intensification trials that, of course, the patients who have less aggressive disease will probably always do better. But it's nice to have this approach as an option for those patients with the most aggressive disease as well. In your opinion, what makes China really unique in the use of ARASENS for treating mHSPC on a global scale?

Yong YANG: I believe the use of chemotherapy, or the use of ARASENS is very important in China. As we know, half of the patients with prostate cancer, and almost all patients with mHSPC, have a Gleason score over eight. Which means, they are much more aggressive compared to the patients in Western countries. That could be a way to raise the survival rate of prostate cancer in China with the ARASENS combination.

Alicia Morgans: I think that's a wonderful goal, and a great opportunity for our patients. How do you view the effectiveness and the safety of ARASENS compared to the other options that you have to treat metastatic hormone-sensitive prostate cancer?

Yong YANG: If we read all the papers from the clinical trials, we will notice that the control arm in the ARASENS clinical trial is ADT plus docetaxel. A 32% reduction in death risk means a lot, because the control arm is ADT plus docetaxel. In other related clinical trials, the control arm is usually ADT or ADT plus bicalutamide. That would be no comparability among them. But it's very interesting that the PEACE-1 study clinical trial showed very promising results when adding docetaxel with ADT plus abiraterone. It also raises my question. Ever since the PEACE-1 study, how to choose for mHSPC patients? Would you share your experience, Dr. Morgans?

Alicia Morgans: Sure. I think that in this case, you highlighted one of the reasons we might choose darolutamide over abiraterone, because we can avoid the use of prednisone in patients with the use of darolutamide. I think it's also convenient to have fewer pills during the day, and fewer things for a patient to remember. And darolutamide is a medicine that you take twice a day, but you don't have to worry as much about taking it on an empty stomach. You don't have to worry about taking the prednisone tablets in addition. And so, these are things that can be somewhat more convenient for patients as well.

And in general also, darolutamide has shown that there are relatively few drug-drug interactions, and relatively fewer adverse events, when compared to placebo at least, when also considering the other androgen receptor signaling antagonists or inhibitors. And so, I think that all of those pieces together make it a nice option for our patients. And although they both are strategies to use to intensify in this disease setting for these patients, convenience can sometimes be one of the key factors for patients.

Yong YANG:  Okay. I got that the ARASENS combination could be convenient and have more safety.

Alicia Morgans: Yes. Yes. And I wonder what your thoughts are? What do you think is the future prospect for ARASENS in China and the opportunity there?

Yong YANG:  Yeah. As we know darolutamide has very strong efficacy for mHSPC, very nice safety, especially fewer falls. And the ARASENS combination, which means plus docetaxel, is a proper option for Chinese patients with higher aggressiveness. So I hope more and more patients with mHSPC in China could all have a way to receive the ARASENS combinations. But we also hope related clinical trials could be done, then we can use darolutamide in earlier stages of prostate cancer. As long as NHT is the proper option, because of its strong efficacy and safety, that's my expectation for the future.

Alicia Morgans: Wonderful. I so appreciate you sharing your experience, and sharing this prostate cancer case from China. Thank you so much for your time and your expertise today.

Yong YANG:  You're welcome. Thank you.