Roundtable Discussion: Grivas Reviews Treatment Goals in Metastatic CRPC

Petros Grivas, MD, PhD

During a Targeted Oncology^TM Case-Based Roundtable event, Petros Grivas, MD, PhD, an associate professor, Medical Oncology, University of Washington School of Medicine, clinical director, GU Cancers Program UW Medicine, and associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center in Seattle, WA, discussed the case of a 75-year-old patient with castration-resistant prostate cancer.

GRIVAS: Do you agree with the patient’s management so far? Would you recommend something else— for example, the addition of a bone-targeting agent, at this point? The question is about what happened so far and going forward.

LIU: This patient is newly diagnosed. At the University of California, Los Angeles, we have the PSMA [prostate-specific membrane antigen] PET scan. He was negative on conventional imaging, but I would recommend a PSMA PET scan. He probably has micrometastatic disease at diagnosis and that would change things, but if there were no PSMA scans available, I would agree with the management with the EBRT and ADT. I would not recommend an addition of an osteoclast-targeting agent at this time. He is castration resistant, so I would consider that. He has an oligometastatic disease, so radiate the areas if he’s having pain and start second-generation hormone therapy.

GRIVAS: That’s a very reasonable approach, treating with EBRT and potential second-generation antiandrogenic agents such as abiraterone [Zytiga] and enzalutamide [Xtandi]. Would you have a preference if you would start either abiraterone or enzalutamide in this case? If so, why?

LIU: No, I don’t. It really depends if he has any comorbidities, and I would generally start with abiraterone, but if he has any heart disease, heart failure, or diabetes, then I would consider enzalutamide.

GRIVAS: Based on the toxicity profile as well as the medical comorbidities for this patient, and you put it in context. My favorite 2 words are clinical and trial. It’s always reasonable to see if there are any clinical trials available.

ZHAO: I agree with initial management. Again, knowing that next-generation imaging modalities such as Axumin PET CT and the PSMA PET are available, but they have not been approved for this indication in newly diagnosed prostate cancer that has not received definitive treatment, I would ask the patient if they want to pay out of pocket or join a clinical trial. We wouldn’t be able to get those PET CTs at that time.

He had a micrometastatic disease and he got radiation. That’s the reality. If you have a patient receiving radiation to the prostate in the STAMPEDE trial, they’re going to benefit. Of course, it’s not going to become a standard of care yet.

GRIVAS: You raised the point of the novel imaging and whether this can be utilized, at which time point, and how it affects outcomes. If you were to start a second-generation anti-androgenic inhibitor, I would say an androgen inhibitor, would you go with abiraterone or enzalutamide, or are there any data in your mind that would influence your decision? Or would you go with chemotherapy?

ZHAO: I wouldn’t go with chemotherapy because of the low-volume disease, low-volume metastases. I agree with Dr Liu. I always consider whether the patient has comorbidities such as cardiovascular disease, congestive heart failure, diabetes, or poorly controlled diabetes. That would affect my decision of abiraterone. Even if they have other issues such as seizure, I would still favor abiraterone over enzalutamide. But in most patients, it’s just a toss. I think either one would be fine.

ARORA: With metastatic disease, I would probably start looking for BRCA gene mutation in someone who has metastatic prostate cancer. There are data on up-front abiraterone use. You have to consider the comorbidities for the patient, such as if they can be on concomitant steroids or not. That’s how I would distinguish it.

There are also data of low-dose abiraterone, so instead of taking 4 pills, you can take 1 pill.1 It’s also similar to progression-free survival in that small trial. Then add a bone remodeling agent, either bisphosphonate or RANK. Sometimes, you get pushback from insurance, so I would just use one or the other.

GRIVAS: At what time point do you do genomic sequencing? You mentioned it for BRCA. Do you do it for other mutations? Do you do it at the time of diagnosis of metastatic disease or later? And do you do somatic testing, germline testing, or both?

ARORA: I do genomic sequencing at the time of metastatic disease; I would do it on the tumor tissue, so I would do somatic testing.

LIU: I always do it at the time of diagnosis, and I always do germline and somatic testing.

ONYSHCHENKO: It doesn’t happen often, but it can be small cell transformation. There is an option to do a biopsy for a relapsed lesion. That’s something to think about, especially if it’s fast growing and PSA is not very high.

KOSIEROWSKI: I tend not to do the germline or somatic testing until they’ve failed initial therapy. Because even if they’re positive, they have to go through initial therapy before you would go with a targeted agent.

GRIVAS: To Dr Onyshchenko’s point, the transformation of small cell is common, but it can happen and it’s more common after antiandrogen therapy of abiraterone or enzalutamide. It’s usually patients who have out of proportion disease on imaging. In this patient, it was even less likely because of the PSA kinetics and the bone disease, but I think it’s a good thought to keep in mind as the patient goes through these therapies.

Regarding the germline and somatic testing, it’s becoming more and more common to do this testing, and we tend to do it earlier on in the disease course ourselves.

SUPERFIN: I usually do it up front with FoundationOne… both somatic and germline up front.

GRIVAS: Does anybody who chose sipuleucel-T from the selection want to comment?

ZHAO: I picked the sipuleucel-T [Provenge]. I thought about abiraterone, but then I can’t recall PSA velocity and doubling time. But it seems that he had symptoms, didn’t he? That would change my mind.

GRIVAS: He had increased right hip pain.

ZHAO: That would change my mind. If he’s minimally symptomatic and he has relatively slow rising PSA, I think sipuleucel-T is the right time to do it. But otherwise, I would go with abiraterone.

SUPERFIN: I thought he’s minimally symptomatic, so I try to use as much therapy possible. It might a good time to try sipuleucel-T because he may not have time later. We can start with that and then go to the next therapy. But it’s the time to try it when he’s minimally symptomatic.

GRIVAS: It sounds like if you have a patient with minimal symptoms or no symptoms, you would think about sipuleucel-T, following the label. This particular patient had hip pain and his PSA was going up relatively quickly. It’s up for discussion, but this PSA rapidly rises and he has symptoms, so you would be worried about sipuleucel-T.

GRIVAS: The National Comprehensive Cancer Network [NCCN] guidelines are broad and they talk about abiraterone, enzalutamide, docetaxel, radium 223 [Xofigo], etc.² Some of you mentioned that if someone is very symptomatic [that would change how you treat]. Is there any differentiating factor here? Nobody picked docetaxel in this case, so there is less enthusiasm about chemotherapy in the context of oligometastatic with 2 hip lesions.

What characteristics in this particular case or whatever characteristic not depicted here would make you pick docetaxel up front?

SHAHIDI: If he has visceral metastases or metastases in long bones making high volume. That was used in the CHAARTED trial [NCT00309985]; they used docetaxel in that setting.

GRIVAS: Dr Shahidi mentioned visceral disease and high-volume disease as per the CHAARTED trial. I just want to make the point that the CHAARTED trial was in the hormone castration-sensitive setting. It noted CRPC, but you extrapolated there the different disease settings. But it sounds like a visceral disease at high volume will make you think docetaxel.

LYOU: I agree. Docetaxel is probably better for the high-volume disease where you need rapid cytoreduction.

GRIVAS: How would you define high-volume disease?

LYOU: For me usually it’s more than 6 or 7 bone metastases at least that are fairly symptomatic; if they have 2 areas of symptoms, like back pain and hip pain at the same time, for example; and the visceral metastases, definitely. That’s what I would define as a high-volume disease or something that needs rapid cytoreduction. [I would use] abiraterone first, if possible, vs enzalutamide. There are some retrospective data showing that if you go from abiraterone to enzalutamide, if you need to sequence the hormone treatments, that tends to work better—nobody seems to know why—as opposed to going from enzalutamide to abiraterone. I’m biased, but personal experience has been that seems to be more successful, abiraterone to enzalutamide as opposed to enzalutamide to abiraterone.

SUPERFIN: There was a trial that showed that it’s better to do abiraterone to enzalutamide vs enzalutamide to abiraterone. It showed abiraterone should be first, and I think I agree with that.

RASILA: I use abiraterone first because it has been my experience that with abiraterone I usually don’t need dose reduction and it’s better tolerated, whereas with enzalutamide, I’ve had to do dose reductions more often than abiraterone. For those reasons, I tend to use it up front.

ZHAO: Based on my experience, it seemed to be more reasonable to try abiraterone because of the better tolerability and because of the new data suggesting the sequence from abiraterone to enzalutamide is more likely to have a better outcome. I have some elderly patients now that have poor tolerance of enzalutamide, so that is always a factor there.

GRIVAS: Two-thirds of you would test for DNA repair deficiency and microsatellite instability [MSI] status. You would do some somatic tumor testing and look for potential targeting options such as PARP inhibitors. Now, we have rucaparib [Rubraca] and olaparib [Lynparza] approved based on different trials. Three people voted for cabazitaxel.

GODFREY: I think cabazitaxel [Jevtana] is certainly reasonable, though they didn’t say whether he responded. I assume since he got 6 cycles of docetaxel, there was a response, but that wasn’t mentioned. Certainly, cabazitaxel is a reasonable next step. I agree with most of the participants that said they would test for MSI and DNA repair deficiency. I said “other” only because at this point, I would probably consider a clinical trial in addition to the above options. I referred similar patients. I think if they’re eligible for [cabozantinib (Cabometyx)] and atezolizumab [Tecentriq], it’s looking interesting. But standardly, cabazitaxel is a reasonable next step.

ONYSHCHENKO: I don’t think there is one best answer here. I’m trying to test now for DNA repair deficiency and MSI at the beginning, but in the case that it’s not done, it usually takes at least 3 weeks and sometimes even a month for results to come back. In this case, it may make sense to start cabazitaxel. Some other consideration is just to do imaging, especially if there is back pain. [Check] if there is local radiation, especially if there is something that looks like compression.

GRIVAS: Imaging looking for compression; clinical trials, as mentioned before. You can do it more than once. You can still do genomic sequencing, somatic and germline. You can potentially start a treatment option and then have the genomic sequencing available.

RASILA: I think the only issue that I have with cabazitaxel is because he had neuropathy already, I would be hesitant due to that. I would check for MSI or any targetable mutations first and see if there is anything else we can use before going to cabazitaxel.

GRIVAS: That’s a good point. It depends on the degree of neuropathy, as you pointed out. I agree it’s a relevant course of duration. How about the neuropathies and any other medical comorbidities?

ADAD: Based on his performance status, I would also consider a palliative care discussion.

GRIVAS: That’s a very important point. I am a supporter of palliative care, especially for symptom management during treatment at some point if the patient can’t tolerate any more therapy. It’s a relevant factor. Performance status, as you pointed out, is over the functionality of the patient and if they can do treatment or not.

GRIVAS: In the guidelines, there’s only 1 option. Cabazitaxel has level 1 evidence....Some people may say neuropathy is better if the patient responds before. We talk about olaparib and rucaparib for DNA repair gene mutations. There are some phase 2 trial data with carboplatin and cabazitaxel, and it would be of interest especially in patients with undifferentiated and neuroendocrine differentiation. Then we have the opportunity to look for MSI status, looking for pembrolizumab [Keytruda].

The other factors are [previous] therapies, tolerability, and patient preference, and all of them can play a role. Is there anything from your practice in terms of what are the 2 or 3 most important factors for you to make a decision in this setting?

SUPERFIN: I think comorbidities and patient performance status are [most important]...prior therapies that he got and how quickly [he progressed]. [Also important is the] molecular profile, if the patient is BRCA positive or BRCA negative, MSI status, and even FoundationOne testing and the availability of clinical trial at nearby institutions based on the FoundationOne profile.

GRIVAS: All these factors are very important. I agree with you.

ELENA: I just want to comment on the radium 223 treatment. If somebody had the progressive disease in the bones only, we could continue second-generation androgen deprivation together with radium 223 followed by the second generation. The disease progressed elsewhere, with visceral metastases. The systemic therapy would be desired and then you go to somatic mutations and what the molecular targets showed based on positive findings.

GRIVAS: The site of metastases is important to you. What if the patient has progression only in the bones vs visceral? The number of metastases? It sounds like probably the pace of disease, as we call it, in conjunction with molecular testing and potential targeted therapies.

ANAD: I would decide between chemotherapy and targeted therapy based on the volume of metastatic disease of more than 5. I would consider chemotherapy and I would give cabazitaxel to patients who did not tolerate docetaxel because, in my opinion, I’ve had patients who tolerated that better. I have a patient who’s been on cabazitaxel for almost 2 years now and doing well.

GODFREY: I would not hesitate to give cabazitaxel. I think it is a different toxicity profile, and I’ve also had patients that tolerated that where they didn’t necessarily tolerate docetaxel very well.

ZHAO: I agree. In my experience with cabazitaxel and docetaxel, in general, cabazitaxel is better tolerated than docetaxel in terms of fatigue and neuropathy.

SHAHIDI: About the question of how I use [cabazitaxel], I usually use 20 mg/m² instead of the 25 mg/m2 that was used in the CARD trial. It’s better tolerated that way.

ADAD: I agree. I use 20 mg/m² as well.

SUPERFIN: I use 20 mg/m². I think I may be lucky, but COVID-19 didn’t affect how we delivered treatment, so I would not change my treatment based on COVID-19, at least not right now.

ELANA: I agree. COVID-19 didn’t change significantly in my practice. And I’m thinking about neuropathy. We provide so much chemotherapy for patients with breast cancer, and most of them have neuropathy as an adverse event. I think it’s all manageable and durable. I use 20 mg/m² as well.

LYOU: The main way this has influenced me is that instead of going for the second antiandrogen, if I can convince patients, I try to go for chemotherapy to break up the sequence between antiandrogens. That doesn’t always happen because a lot of people have this stigma around chemotherapy, but it’s possible that it’s been able to increase the conversion or convincing patients to go for the chemotherapy first before moving onto the second antiandrogen.

ZHAO: I have been using 20 mg/m² of cabazitaxel for years and I like that. It’s very tolerable. But I also have noticed that if we do use 25 mg/m² in certain situations, we can achieve a better PSA response. Of course, it is hard to measure the imaging response, but the PSA response sometimes can be a pretty good surrogate for how a patient does. I have patients that I have upped and increased the dose from 20 to 25 mg/m² every once in a while, when they have disease progression on 20 mg/m². I get some objective response, and that’s something I’m waiting to do recently.

_References:

_{1. Szmulewitz RZ, Peer CJ, Ibraheem A, et al. Prospective international randomized phase II study of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer. J Clin Oncol. 2018;36(14):1389-1395. doi:10.1200/JCO.2017.76.4381}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2021. Accessed Aug 5, 2021. https://bit.ly/3mcUrQF}