Choosing AR-Targeted Therapy in CSPC

Monitoring Responses to Novel Hormonal Agents in Metastatic CSPC

During a live virtual event, Daniel C. Danila, MD, discussed how to treat a patient with de novo metastatic castration-sensitive prostate cancer and monitor for disease progression.

Targeted OncologyTM: How do the recent data about docetaxel and abiraterone (Zytiga) up-front in metastatic castration-sensitive prostate cancer (mCSPC) affect your practice?

DANILA: The phase 3 PEACE-1 trial [NCT01957436] presented at the 2021 European Society of Medical Oncology [ESMO] Congress demonstrated that using docetaxel in addition to abiraterone up-front improved overall survival [OS], and that’s a great addition to the armamentarium.1 What I haven’t seen it compared is with abiraterone alone, except in different parallel studies. And I would choose to start docetaxel and abiraterone for toxicity profile. I think for a healthy young patient with aggressive, maybe visceral disease, starting with a combination would be a wiser choice. But I personally still give abiraterone with a LATITUDE [NCT01715285] type of approach or give enzalutamide [Xtandi] or apalutamide [Erleada].

I think the docetaxel/abiraterone combination is going to catch on as an option. I This is the first data from October ESMO 2021, so I think we have to [wait to] understand these data a bit better and see some comparison to abiraterone alone.

How would you administer the combination and monitor disease progression for patients on this combination?

I think [patients] tolerating [abiraterone] will encourage you to add it on, but I think the PEACE-1 trial started both from the beginning. We knew that abiraterone has a better time to progression compared with docetaxel. But, that was obvious because you do 6 cycles of docetaxel, and then after you see progression, you start abiraterone; abiraterone is continuous to progression.2 Most progression on the patients on the CHAARTED trial [NCT00309985] was determined by PSA [prostate-specific antigen], so when adding abiraterone, even after docetaxel, patients may show a PSA decline initially and then their PSA rises.

I personally wait for radiographic progression, and that’s the other way of doing it, but choosing taxane for the initial option is interesting. There is a very important discussion for aggressive and visceral disease in fit patients that you want to have an initial response. I think that’s where I mostly use it at this point.

How do you monitor a patient receiving apalutamide?

[For a] patient receiving apalutamide, I wait for imaging to confirm progression. If I see a quick rise in PSA, I become very uncomfortable, and I would order imaging sooner. But remember, PSA by itself is not a good biomarker for progression or to monitor treatment responses. So, I’m trying to be more objective. Symptomatic disease is the most important [factor], and progression of imaging is the second most important to me, and PSA’s a factor [as well].

Is there a role for circulating tumor DNA (ctDNA) monitoring in patients receiving hormonal agents?

I don’t think we have a biomarker in ctDNA for [detecting] response to treatment. It may be very good for treatment selection, and if you’re talking about tumor burden DNA, [if] it’s very low levels, seeing it wash off may be a good prognostic [factor], but I don’t use it in clinic. We are still trying to evaluate it for treatment selection, to understand how prevalent genetic differences are versus tissue-based genetics.

Do you continue to do imaging regularly during treatment, or is PSA a bigger factor in monitoring for disease progression?

If I see a good response, I’m not going to rush into ordering scans. If I see a rise in PSA, I might order scans sooner, but I would do scans anyway at 9 months if I don’t see any PSA rise, just to have a good bit of background for updated treatment response. And remember, if you don’t do scans except when you see symptoms, you might get a CT scan, bone scan, or PET scan that could show a refracture that the patient got from just bumping into things. So, I think I would update the imaging from time to time, maybe 9 months if it’s a great response, but I will do it more often if I see a [rising] PSA or some symptoms for focal therapy.

What imaging do you use to determine disease progression? Do you use next-generation scans such as PSMA (prostate-specific membrane antigen)-PET?

I personally use the FDG [fluorodeoxyglucose] PET scan, because that’s clinically demonstrated to correlate [its parameters] with OS for castration-resistant disease.3 The PSMA-PET scan is good for identifying lesions, but I don’t use it to compare PSMA SUV [standardized uptake values], because those have not been validated. I don’t know what the androgen deprivation therapy [ADT] or apalutamide will do to those SUVs. It might be increased, or the PSMA expression might decrease it artificially without tumor growth. So, for bone lesions, it’s very hard to appreciate them on a bone scan, or a CT scan except if you see 2 or more bone lesions. I sometimes use an FDG PET to identify oligometastatic progression and target it more specifically to try to get it in focal therapy and maintain systemic therapy.

What changes do you think should be made in practice for patients with de novo mCSPC?

We already have 4 options for de novo mCSPC; I think choosing the right one is important.

The docetaxel/abiraterone combination is from quite a large randomized phase 3 trial with 4 arms that combine in 2. So, those are pretty good data that show survival benefit, so I think up-front, it proved to show OS benefit there.1

Because of the long interval between the 6 cycles in the CHAARTED trial, I may re-use the docetaxel in castration-resistant disease. The safety profile [should be considered]; you might start on an agent and change to [an agent with better] tolerability. I think sequencing is still [an important] question; what to use first, and then how to switch.

Are there any studies that include patients with ECOG performance score of 2 or higher?

I think there are studies including patients with ECOG performance 2. I think performance score 3 and 4 are hard to start on a study, because the studies try to use better performance, or at least 6 months life expectancy.

As a clinician, I would adapt to that, and if the ECOG score or the patient’s frailty is related to the cancer, I might be more aggressive. If a patient is very elderly and sick, I might not start a combination, and definitely not docetaxel. As clinicians, we understand that, and we adapt to that, and I might start single-agent ADT for 3 or 4 months, and see if they improve their performance status, because that might get them in a clinical trial range. I think sometimes these trials don’t answer what to do in real life. As clinicians, we have to address that.

References:

1. Fizazi K, Galceran JC, Foulon S, et al. A phase III trial with a 2x2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: overall survival with abiraterone acetate plus prednisone in PEACE-1. Ann. Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/j.annonc.2021.08.2099

2. Abiraterone (Zytiga). Prescribing information, Centocor Ortho Biotech, 2021. Accessed February 18, 2022. https://bit.ly/3HX2Lfg

3. Jadvar H, Desai B, Ji L, et al. Baseline 18F-FDG PET/CT parameters as imaging biomarkers of overall survival in castrate-resistant metastatic prostate cancer. J Nucl Med. 2013;54(8):1195-1201. doi:10.2967/jnumed.112.114116