Neeraj Agarwal: Thank you for having me, Zach. It's exciting to see so much happening in the metastatic hormone-sensitive or metastatic androgen pathway modulation sensitive prostate cancer. It will take some time for us to get used to this technically correct term, androgen pathway modulation sensitive prostate cancer, APMS prostate cancer, and I love this terminology because this avoids the word castration and I have been wanting to do that for a long time, so just wanted to open this discussion with the emphasis on avoiding castration.
Zachary Klaassen: That's important.
Neeraj Agarwal: So doublet versus triplet, as we know, ADT plus docetaxel chemotherapy in CHAARTED study and then STAMPEDE trial showed superiority over ADT alone. Then we saw a slew of trials reporting, starting from STAMPEDE, then ARCHES, then TITAN with apalutamide, and then triplet therapies, RSN trial and PEACE group presented the trial with triplet therapy, abiraterone plus docetaxel chemotherapy. Then most recently, we saw the ARANOTE trial with ADT plus darolutamide versus ADT monotherapy.
The bottom line from all this trial is ADT plus ARPI or ADT plus docetaxel improved survival versus ADT alone, except one of the most recent trials. I think that as data will mature, we'll see maturation of overall survival. But the bottom line is that, if you ask me to give a message today, ADT plus ARPI or ADT plus docetaxel improves survival versus ADT generally. Then we saw this triplet therapy trial where ADT plus ARPI plus docetaxel showed improved outcomes compared to ADT plus docetaxel.
The question whether ADT plus ARPI plus docetaxel is better than ADT plus ARPI is not answered yet, an Alliance trial is asking that question right now. We don't have that. Now, we have two options in the clinic in the absence of that answer, which is when a patient comes to me with metastatic hormone-sensitive prostate cancer and I have ADT plus ARPI versus triplet chemotherapy, ADT plus ARPI plus docetaxel, how do I approach my discussion?
First thing I do is I start my patients on bicalutamide and androgen deprivation therapy and order multiple tests, and I'll come to the tests in a moment. I start them on treatment right away because I don't want them to have more complications from their metastatic prostate cancer in general. If somebody has slowly rising PSA level, maybe not, but most patients who have been referred to me with some imaging finding of metastatic disease, I start them on bicalutamide plus ADT.
The scans I get is mostly CT scans, bone scans, or combination of conventional scan or PSMA PET scan. Most of the time PSMA PET scan is already done by the local physician, which has led to the diagnosis of metastatic disease. In addition, I do NGS testing for all my patients through CLIA certified lab. Tumor NGS tissues preferred. I make sure that I get the blood for ctDNA testing before giving them the Lupron injection or Eligard injection, or let's make it more generic, GNRH agonists or antagonist injection, because once PSA goes down very quickly, it is hard to get ctDNA, so that's something to keep in mind. I do germline testing to make sure I know the patient is not carrying a germline pathogenic variant. That is the overall testing profile other than DEXA scan and some cardiac workup, if they have predisposing risk factors, hemoglobin A1C and all that. Pretty good number of tests.
I have patients come back after one month, they are already leuprolide or GNRH agonist or antagonist. PSA is going down nicely and this is a time to discuss more. They're coming out of their initial shock of being diagnosed with metastatic prostate cancer and now they're more ready to discuss. At this time I look at the CT scans, bone scans, PSMA PET scans, all the scans together, look at the NGS testing profile, and sometimes answer is very straightforward. Low volume disease, patient have SPOP mutation, patients are very frail, older patients who obviously are long-term diabetic who are obviously not candidate for chemotherapy, the answer is very straightforward, ADT plus ARPI.
The choice of ARPI is pretty much driven by abiraterone versus non-abiraterone, amides. Abiraterone stopgap M1 analysis have shown, and some of the data from Dr. Marty shown from VA Hospital, that abiraterone may be less efficacious in older patients, 75-year-old plus. Even earlier, we don't have level one evidence, but it is generally a consensus right now that amides may be better than abiraterone from efficacy perspective. But abiraterone is inexpensive, and in absence of level one evidence, I consider them all equal unless there are obvious contraindications.
I talk about ADT plus ARPI, and mostly driven by copay, drug interaction and so on. Some have high liver function. Liver function tests are abnormal, so you can choose one ARPI. If they're on anticoagulation, you can only use this ARPI. Then of course, the copay. What is covered? All of that, that's the discussion about ADT and choice of ARPI.
When do I choose chemotherapy? In my clinic, it's very personalized. If I see visceral metastases in the liver, liver not lung, lung metastases are different trajectory and these are about 7, 10%, maybe more if they have high volume disease, it's pretty straightforward. If you look at the forest plots of subgroup analysis of the ARCHES trial and the TITAN trial, that's the only subset which doesn't seem to benefit by adding ARPI. That's a subset which is clear in my mind that I'm going to offer them ADT plus ARPI plus docetaxel chemotherapy if they're eligible.
Next is tumor suppressive gene loss. We saw consistently in the PTEN deficient patients, if you look at the overall trial, the CAPItello-281 trial, PTEN deficiency by immunohistochemistry, 90% or more loss, which probably equate to a pretty good degree of PTEN loss, the median PFS with ADT plus abiraterone was 25 months. Median PFS, rPFS, when you look at the PTEN loss of 99 to 100%, 22 months. That is exactly half of what we usually see with these agents.
Zachary Klaassen: That's right.
Neeraj Agarwal: That basically tells me that if patients had obvious PTEN loss, and that's a great thing about doing immunohistochemistry now rather than waiting for the CAPItello-281 approval to come through, because these big losses may be missed by NGS testing. So immunohistochemistry is a very easy test to do, so if you have PTEN loss by immunohistochemistry of high degree, I cannot really rely on ADT plus ARPI alone. Either I need capivasertib, if it is approved or when it is approved, or chemotherapy. This is pretty straightforward.
Then RB1 loss, for example, that's another set of patients who really have bad prognosis, do not do well on ADT plus ARPI, and we may not have the opportunity to give them second line therapy if they progress. They progress very quickly. That's where I use. RB1 loss, PTEN loss for sure, and P53, I don't really look at P53 alone. P53 present with something else, I tend... This is my personal practice. Of course, somebody has really high volume disease. We are all clinicians. Low volume, high volume disease is defined at four or more bone metastasis. There's nothing beyond which is being used. Now, how about a huge lesion covering your entire femur or pelvis compared to four small spots? So obviously, we have to use our clinical judgment.
If patient present with baseline pain, for example, baseline pain is an independent bad prognostic marker. If patient presents with bone pain, they don't do as well on ADT plus ARPI. These clinical features are also very helpful. So if I see, if you look at the bone scan, it's all metastatic all over, obviously patient need as much as possible. Patients presenting with pain, bone pain especially, patient needs something else beyond ADT plus ARPI. For me, until I have all these biomarkers, and if your biomarker is pretty straightforward, for BRCA1, BRCA2, I'm going to use abiraterone plus niraparib. If enzalutamide or when enzalutamide plus talazoparib get approved, hopefully for all HRR mutation positive patients, I will use that combination. If we have capivasertib approved, I will use capivasertib.
But until then, and for many countries, many of our patients, we may not have those things available. In those patients, I think really high volume disease or de novo disease, patient has bone pain, cachexia, weight loss of high degree, we see young patients sometimes presenting with a lot of weight loss and then they get a test done, and in fact, multiple cases I've come across, I like to use triplet therapy. Of course, those tumor suppressor gene loss, PTEN loss, high degree, especially immunohistochemistry and RB1 loss, I like to use chemotherapy not because I have the data, because I know they don't do very well on ADT plus ARPI. If I add something else, if they can take it, why not?
Zachary Klaassen: Yeah. That's a fantastic playbook, Neeraj. The one question I want to ask you before we wrap up, likely coming down the pipeline, PSMAddition, lutetium in this metastatic castrate-sensitive or hormone-sensitive disease space. In that trial, there was sort of every ARPI was allowed as that ADT plus ARPI plus lutetium. When we see these patients and we have a big PSMA signal, we're going to think about lutetium, do you think the ARPI matters in terms of the side effect profile? We all know they work pretty well and we have the benefit of lutetium. In that discussion of which ARPI to select, how are you going to have that with your patients?
Neeraj Agarwal: The good thing about lutetium treatment is it is ARPI agnostic, I think. Really, I have used lutetium with every ARPI, with amide versus CYP inhibitor right now, abiraterone plus enzalutamide and mCRPC. I really have not seen any problems, so that's a great news. Regarding personalizing treatment, when somebody say lutetium is approved in first-line based on PSMAddition data, and now we have that in the clinic, how can we avoid side effects?
I think one question will always come up, and has already come up, is patients who have undetectable PSA, PSF less than 0.2 nanogram per mil. After two or four cycles of lutetium, will they get benefit with more lutetium? It's likely not. That extra lutetium is probably going to go to the area where it doesn't have to go, like salivary glands, bone marrow, spilling in the kidneys, causing kidney renal dysfunction and so on. That's one thing I will keep in mind, that if patient have great response, I will probably not continue lutetium. Currently awaiting data from other studies to see how we can personalize lutetium from that perspective.
Second, ARPI. I usually don't stop ADT plus ARPI unless patients have very severe symptoms. I have had patients, younger patients who have severe depression to the extent that they couldn't continue working full-time, losing their insurance and so on, which can impact their life if they cannot afford medications. So yes, in those cases or patients' wishes, which is always very important, we have taken breaks. But I tell my patients, "Let's get to the six-month PSA." If PSA less than 0.2, as you said, happens in about 50% of patients, I feel very comfortable taking the break.
The third strategy is stopping the ADT and continuing the ARPI in those patients who have severe hot flashes, mostly younger, whose testosterone probably was 700, 800 nanogram per deciliter, and we suddenly brought them to less than 50. Those patients can have severe fatigue, severe hot flashes, debilitating side effects. I've personally found if I just take a break from androgen deprivation therapy and continue the ARPI, those patients feel better based on my personal experience.
We do have LIBERTAS trial going on, and in the LIBERTAS trial, we are asking the question of in patients who have achieved a PSA level of less than 0.2, they are randomized to continuation of ADT plus apalutamide versus only apalutamide. Then we are assessing hot flashes and other quality of life domains only on apalutamide. There's a URTC trial going on where all the medications are being stopped, so complete discontinuation of all drugs and then restart per investigator discretion, so pretty pragmatic trial. I think these two trials will tell us more about how safe it is to take a break without any obvious reasons. If there is obvious reason, severe side effects, yes, we should take a break off any medication. But if there are no reasons, I tell my patients, "Look, these are life-prolonging therapies and I'm very hesitant to take a break unless you really want me to do that."
For now, I would suggest, in absence of symptoms, we should not take breaks until we have results of these trials. Of course, if we have to, I would like to see the PSA of less than 0.2 and taking a break from any of these medications is possible. Lutetium in the context of PSMAddition type protocol treatment. Docetaxel, there's a limited duration therapy anyways. You can take a break from ARPI, you can take a break from ADT, you can take a break from all of this treatment. Ultimately, this is personalization from side effect perspective, that's how I describe it.
Zachary Klaassen: Neeraj, we covered a lot of great information today. I can't thank you enough. Doublet versus triplet, very important discussion and getting more complicated in an exciting way for our patients with more options. Thank you for joining us on UroToday.
Neeraj Agarwal: Thank you.