CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Nurses: 1.00 Nursing contact hour
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 16, 2023
Expiration: August 15, 2024
Prostate Cancer Disease Spectrum
Alicia K. Morgans, MD, MPH:
Prostate cancer diagnosis may occur at various stages, and progresses through different pathways.3,4 A rise in PSA levels following definitive therapy for localized or locally advanced disease is considered a biochemical recurrence, after which, response to ADT determines whether it is CRPC or HSPC.
Patient Case: mHSPC
Alicia K. Morgans, MD, MPH:
We are going to frame our discussion of mHSPC around a case study of a 72-year-old man who presents with fatigue, lower back pain, and weight loss. His PSA is 655 ng/mL. He had a biopsy showing Gleason 5+5 disease and conventional imaging showed metastatic disease. He is not well, but keeping in mind he is 72, Dr. VanderWeele, when you see a patient like this, what do you imagine is the current SoC for mHSPC?
Standard of Care in mHSPC
David VanderWeele, MD, PhD:
The SoC for patients with mHSPC is a doublet or a triplet therapy containing ADT and ARSI with or without chemotherapy, based on several phase III clinical trials (LATITUDE, STAMPEDE Arm G, ARCHES, ENZAMET, TITAN, ARASENS, PEACE-1).5-11
In this particular patient case, I would want to know more about the extent of his disease, but it sounds like high-volume disease, with grade group 5, and very high PSA. This is the type of patient that I generally encourage to think about triplet therapy, being symptomatic upon diagnosis, with what sounds like pretty aggressive disease. Because of the patient’s weight loss, we may also propose to start with hormone therapy and see how they do, and then think about if we can add in docetaxel on top of that.
Alicia K. Morgans, MD, MPH:
One message to emphasize is that ADT alone is not the SoC for the vast majority of patients with mHSPC. Dr. Schweizer, would you think about using triplet therapy in this patient, and if so, who is the best candidate?
Michael T. Schweizer, MD:
I at least mention triplet therapy to anybody with mHSPC, particularly for patients who present with de novo metastasis. This group of patients comprised the entire population of the phase III PEACE 1 trial11 and 86% of the phase III ARASENS trial,10 and we know they are higher risk patients to begin with.
ARASENS: Overall Survival by Disease Volume
Michael T. Schweizer, MD:
I struggle with the question of whether disease volume should dictate whether patients get triplet therapy vs doublet therapy. A post hoc subgroup analysis from the ARASENS trial12 showed a similar magnitude of survival benefit for triplet darolutamide plus ADT plus docetaxel vs ADT plus docetaxel regardless of disease volume (high-volume HR: 0.69; 95% CI: 0.57-0.82; low-volume HR: 0.68; 95% CI: 0.41-1.13). Survival benefit was also similar for high-risk and low-risk patients (high-risk HR: 0.71; 95% CI: 0.58-0.86; low-risk HR: 0.62; 95% CI: 0.42-0.90). I do not think triplet therapy is right for everybody, but if I have a patient who is relatively fit and they express that their main desire is to prolong survival, I would consider triplet therapy. One outstanding question is whether or not a similar study design would still show the darolutamide triplet as superior to the combination of an AR inhibitor plus leuprolide. We have only compared the triplet to AR inhibitor plus docetaxel, and before the ARASENS data, I worked under the assumption that ADT plus either chemotherapy or AR inhibitors had similar outcomes.
CHAARTED 8-Year Follow-up: Overall Survival by Disease Volume
David VanderWeele, MD, PhD:
I think it is helpful to note that it is not a question of chemotherapy now or never; rather, it is a question of chemotherapy now vs later.
I would agree that triplet therapy is a reasonable option for de novo metastatic disease but not necessarily for recurrent disease (metachronous presentation). I am not encouraging docetaxel in all patients with low-volume metastatic disease because of the phase III CHAARTED trial results (no OS benefit observed for ADT plus docetaxel vs ADT alone in patients with low-volume mHSPC; HR: 1.04; 95% CI: 0.70-1.55; P = .86).13,14 Putting together CHAARTED and STAMPEDE,15 I think patients with low-volume recurrent disease benefit the least from the addition of docetaxel.
ARASENS: OS by Metastatic Stage at Diagnosis
Michael T. Schweizer, MD:
We know that de novo metastasis is a high risk feature, just like having high volume disease. It is difficult to compare the subgroup analyses between studies in an attempt to try to understand which patients may really benefit from the addition of docetaxel. But I think the data have shown consistent outcomes with triplet therapy in this patient population. In the phase III ARASENS trial, triplet darolutamide plus ADT plus docetaxel vs ADT plus docetaxel showed significant OS benefit in patients with de novo mHSPC (HR: 0.71; 95% CI: 0.59-0.85).10
PEACE-1: Triplet Therapy With Abiraterone Plus Docetaxel Plus ADT vs Docetaxel Plus ADT in de Novo mCSPC
Michael T. Schweizer, MD:
Similarly, in the phase III PEACE 1 trial, triplet abiraterone plus ADT plus docetaxel vs ADT plus docetaxel showed significant benefit in rPFS (HR: 0.50; 99.9% CI: 0.34-0.71; P <.0001) and OS (HR: 0.75; 95.1% CI: 0.59-0.95; P = .017).11 Again, I do not give docetaxel to every patient, but I tend to be more in favor of docetaxel for patients with de novo metastatic cancer, especially if they are young and fit, and really want to be aggressive. We need more studies to clarify exactly which patient populations need triplet therapy vs those only needing a doublet regimen, since I do think that many patients would probably do just fine with abiraterone plus ADT vs the more intensive triplet therapy.
Alicia K. Morgans, MD, MPH:
I agree and I take the same approaches you both mentioned. For anyone who is fit for chemotherapy, especially if they have de novo mHSPC, I certainly push in that direction. If they have metachronous presentation, I will talk about chemotherapy, but I do not necessarily push as hard. I use a stepwise approach to add in AR targeted agents starting approximately 1 month after ADT and then add chemotherapy after that for patients I think may benefit. I think that adding them sequentially lets patients adjust, come to a new normal, and figure out their adverse effect profile, and then maybe find that it is more tolerable and move on to the next component of the regimen.
ARASENS: Safety
Alicia K. Morgans, MD, MPH:
If a patient is fit for chemotherapy, I think that we can manage the toxicities of docetaxel in a less disruptive way. They do lose hair, but I have many patients who continue to work, go out, and do things that they normally do, even if they do have to take a nap in the afternoon or take things a bit more slowly, especially as they get further along in the cycles. Dr. Schweizer, do you think that the toxicities are much more challenging when we add in docetaxel with triplet therapy?
Michael T. Schweizer, MD:
The main thing I have noticed is more dermatologic adverse events with darolutamide, which was reported in the ARASENS trial.10 I have had several patients with some significant rashes, but otherwise, I do not think there is anything too problematic in terms of using the combination.
David VanderWeele, MD, PhD:
I agree. I have had 80-year-old patients get through triplet therapy without much difficulty and they often comment that they are doing much better than they expected in the middle of the chemotherapy.
PSMA PET Imaging in Patients With Early Biochemical Recurrence After Prostatectomy in Advanced Prostate Cancer
Alicia K. Morgans, MD, MPH:
Some of our patients with HSPC are metastatic by prostate-specific membrane antigen (PSMA) PET scan only, with a very low volume of disease beyond the prostate. What are you doing when you see patients that are negative by conventional imaging but show metastases with PSMA PET? Do you use metastasis directed therapy (MDT) for oligometastatic treatment, using radiation and other approaches to potentially achieve cure for those patients?
Selected Randomized Phase II or III Trials in Oligometastatic Prostate Cancer
Tanya B. Dorff, MD:
If follow-up PSMA PET shows an isolated lymph node outside the previous treatment field or an isolated bone metastasis, I think most of us are incorporating metastasis directed radiation. There are trials that have looked at radiation alone, such as phase I POPSTAR, phase II STOMP, and phase II ORIOLE suggesting efficacy for oligometastatic disease and potential to delay systemic ADT,16-18 but the open question in my mind is, because so many previous studies have shown radiation plus ADT yields better outcomes than radiation alone in definitive and salvage settings, will we see the same trend emerge when using our PSMA PETs to do MDT?19
Michael T. Schweizer, MD:
I am using site-directed radiation for many of these patients, although I am skeptical that we will cure anyone. In my mind, the main advantage is that you probably provide a longer lag time in terms of when you will need to start systemic therapy. We do not have any long term data showing that site directed therapy is improving more important clinical outcome endpoints such as metastasis free survival (MFS) or OS. However, if you can radiate 1 metastasis that you find on a PET scan and delay the need for ADT, that is a good thing and I do it frequently.
Alicia K. Morgans, MD, MPH:
So without changing the final outcome, maybe we are changing the disease trajectory, which might still be meaningful.
David VanderWeele, MD, PhD:
There are several ongoing trials in the oligometastatic, oligo-recurrence, or salvage setting and I would recommend that you consider those for your patients.20,21 Outside of trials, I do use MDT or encourage patients to think about it, and I tell them there is not a lot of data, although it seems to be somewhat promising in terms of disease control.
Alicia K. Morgans, MD, MPH:
I have a group of patients where we are combining ADT or targeted-agent MDT plus radiation to the prostate and to the pelvis. Therapy stops at 2 years, and we will watch for testosterone recovery; this sometimes leads to undetectable PSA levels, even though testosterone is recovering.
Incorporating PSMA PET Imaging into Treatment Decisions
Alicia K. Morgans, MD, MPH:
How do you interpret older data in light of PSMA PET, considering that older trials all used conventional imaging?
Tanya B. Dorff, MD:
A colleague recently told me that there are no patients with PSMA PET–negative scans with rising PSA, especially once you hit a certain PSA level, but in my practice there still are. I think this means that there is still a role for intermittent ADT, and possibly an intensified strategy now with the results of the EMBARK trial discussed below. But for PSMA PET–positive disease, we are treating before having data to guide us.
The phase III INDICATE (EA8191) trial (NCT04423211) is in the early stages, enrolling patients who have not yet had salvage radiation to the prostate bed and pelvic lymph node basins. This trial is going to ask a very important question about what to do with extrapelvic PET scan findings when giving salvage radiation and ADT. It is also asking the question of whether PET scans can be used to identify patients who would benefit from local or systemic SoC treatment intensification. We need more studies like this, and people need to realize that we do not know if the best treatment is to radiate everything seen on a PSMA PET scan. These trials need to be supported to answer questions about how to better use PSMA PET in our practice.
Rana R. McKay, MD:
There has also been discussion about false positives with PSMA PET scans. Patients can have their entire treatment trajectory change based on PSMA PET results, without being offered local therapy or by being subjected to longer or intensified courses of hormonal therapy. We do not have prospective data to guide the best treatment strategy for individuals that are PSMA PET positive but conventional imaging negative. A lot of ongoing clinical trials are looking at the role of MDT, including different iterations of hormone therapy, whether it be short course or longer course, intensified or not, that are going to be really critical in the field. It is my suspicion that in 5-10 years, the term “conventional imaging” is going to mean PSMA PET.
Importance of Treating the Primary Prostate Tumor
Michael T. Schweizer, MD:
I want to emphasize the importance of treating the primary prostate tumor in patients with PSMA PET–positive prostate cancer. If we have a patient whose initial screening shows low-volume disease by PSMA PET that would not likely be seen on conventional imaging, in my mind, the data are insufficient to say that we should not treat their primary tumor at this point. Ultimately, there are a lot of data showing that patients who have no cancer on CT and bone scans are going to benefit from local therapy, and PET imaging should not change what is considered the SoC. If anything, you might want to intensify treatment by treating the oligometastases too. I have seen some examples in the community where they decided not to operate or offer radiation to the prostate because they found small lymph nodes on a PSMA PET scan. My view is that the data are insufficient to de-escalate care based on PET imaging alone.
David VanderWeele, MD, PhD:
I agree. For patients with de novo metastatic, conventional imaging–negative, PSMA PET–positive prostate cancer, I think about the prostate and try to forget that the PET imaging was done, and then take things from there. It may depend a bit on what the images actually look like, but I agree with you; we have so much data for conventional imaging–negative patients that we should make clinical decisions based on that.
PSMA PET Imaging as SoC
Alicia K. Morgans, MD, MPH:
When do you think PSMA PET will become the SoC vs conventional imaging?
Rana R. McKay, MD:
PSMA PET is becoming increasingly used, and I think one of the biggest factors is access and coverage. Access is variable between academic and community practices. Effective centers have a team of individuals that can help with the prior authorization process and getting approvals for patients. Some practices do not necessarily have the staff dedicated for these things, and it can be very cumbersome to fight those battles.
Tanya B. Dorff, MD:
Outside of the United States, PSMA PET is already the standard, but within the United States, I do hear that there is still lack of access. However, I think probably at least one half of patients with rising PSA in this scenario get a PSMA PET scan, so it is definitely common.
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