Roundtable Discussion: Experts Look at Treatment Options for Patients With Metastatic Castration-Resistant Prostate Cancer

During a Targeted Oncology Case-Based Roundtable event, Sandy Srinivas, MD, medical oncologist, Urologic Specialist, Genitourinary Specialist, professor of Medicine (Oncology)of Urology Clinical Research Group Leader, Urologic Program Stanford Healthcare, served a one of the moderators of a discussion around a 75-year-old patients with metastatic castration-resistant prostate cancer (mCRPC).

Nicholas J. Vogelzang, MD

Nicholas J. Vogelzang, MD, chairman, Medical Oncology, Comprehensive Cancer Centers in Las Vegas, NV was the comoderator, offering a community oncology perspective.

GOWDA: In my practice we don’t usually add bone-modifying agents unless [the patient is] castrate resistant. We don’t use it for castration-sensitive [patients], but then you do occasionally encounter patients with a significant osteoporosis. For them we give the agents but not very frequently—more like osteoporosis treatment than metastatic cancer protocol.

SRINIVAS: [For everyone else,] is this the time you’re introducing a bone-modifying drug [for a patient like this]?

SIBLEY: It would be, and that’s just because of previous trial data showing evidence of improvement in skeletal-related events and fractures in patients with metastatic disease. I tend to introduce these medications early but I use them in combination with other risk factors like age, history of osteoporosis, fall risk, and other factors. I traditionally used a lot of bisphosphonates, and that’s what I have more experience with. It’s not that I have an issue with denosumab [Xgeva]. I’m just more comfortable with bisphosphonates.

VOGELZANG: I don’t think bicalutamide’s a great idea. There was the TERRAIN study [NCT01288911] of bicalutamide vs enzalutamide and enzalutamide soundly trumped bicalutamide.1 The usual choice here would either be abiraterone [Zytiga] or enzalutamide [Xtandi].

Most patients aren’t going to jump at docetaxel [Taxotere], but sipuleucel-T [Provenge] would be reasonable. Radium 223 [Xofigo] would be reasonable, but the patient isn’t that symptomatic, but I’ve done a lot of combinations with abiraterone and radium, although the package insert says you should not. I generally tend to do that, but I’m very careful to give bone drugs because the bone fracture rates do go up when you give abiraterone and radium. So I must give bone drugs with 2 agents.

SRINIVAS: The National Comprehensive Cancer Network has many recommendations in category 1, and abiraterone makes it to category 1. You have enzalutamide as an alternate AR-targeting drug. Docetaxel makes it to category 1, and then under certain circumstances, sipuleucel-T is a category 1 recommendation.

How would you all pick between these choices for your patient with CRPC?

MAITY MUKHERJEE: At this point I’m trying to buy time for my patients, so I would start off with either abiraterone or enzalutamide because patients generally don’t prefer to go into chemotherapy in the first line and I prefer to keep that down the road. But if it’s a younger patient with aggressive disease, with a Gleason score 9 or above, then yes, I may at times choose that in the first line, but generally I would prefer the oral agents over the intravenous ones at this point.

SRINIVAS: Do you have a choice between abiraterone vs enzalutamide?

MAITY MUKHERJEE: Not really—mostly [it depends on] certain conditions, like whether a patient has a history of seizures or a low tolerability to steroids. These are unusual, but I chose abiraterone, because I generally start with abiraterone unless there is a reason to do otherwise.

MITIN: I’m a radiation oncologist, so I usually don’t make those decisions in my practice. My colleagues, medical oncologists, typically go with either abiraterone or enzalutamide. I heard some of my medical oncologist colleagues say that there are data to suggest that [a patient like this is important to address], so they want to start with abiraterone so that they can switch to enzalutamide when the abiraterone fails. I think it does come from kind of a retrospective analysis, so it’s not practice guiding, but that’s what they use.

RASILA: My preferred option is abiraterone with prednisone, unless the patient has poorly controlled diabetes or liver issues, which I’ve usually not had any major problems with using abiraterone. I usually do a trial of enzalutamide before moving on to chemotherapy, or other agents [if they failed abiraterone].

FANG: I think we should be testing when the patient has a BRCA2 mutation or MSI mismatch, because a PARP inhibitor in my experience is highly effective in those patients who have a BRCA2 mutation. My impression was that at least 20% of [patients] with metastatic CRPC have BRCA2 mutations.² Those [individuals] will likely respond very nicely to a PARP inhibitor.

I would use olaparib [Lynparza] in a patient with a BRCA2 mutation, and [when I’ve used olaparib, I've seen quite an impressive drop in PSA levels]. I will not deprive the patient of an opportunity to be treated with novel therapies. I think it’s not wrong to give a patient cabazitaxel, even though I didn’t choose it, but that is a recommendation for this setting.

KESHAVA PRASAD: I chose cabazitaxel because I’ve seen some patients in this same setting and they responded quite well to it. I would still get next-generation sequencing done to look for any targets, including immunotherapy or BRCA inhibitors, and things like that. [This is my choice] because [the patient in this case] is having progressive disease and prior studies have shown that [patients] who progress after docetaxel responded to cabazitaxel.³ That’s what I would choose at this time and then, later, have radium and other treatments in reserve.

KRIJANOVSKI: I picked chemotherapy, then I would pick up cabazitaxel at 20 mg/m². I think this is the right choice at this point. I’m not clear whether prednisone will help at this time, but it will depend on patient performance and their wishes.

I just want to kind of reflect a little bit on the early bisphosphonate question. I know you usually go by a DEXA [dual-energy x-ray absorptiometry] scan, and if the T score was –2 or less, then I would use something like denosumab every 6 months.⁴ However, if there is something like osteoporosis, at that point my choice would be denosumab, then repeat as a manager to a kidney problem in the older population, but it depends on insurance. Sometimes insurance doesn’t cover that or bisphosphonates.

VOGELZANG: [My choice would not be abiraterone and prednisone]. The response rate [in prior studies] after enzalutamide failure, when you put [patients] on abiraterone plus prednisone, was minuscule. Therefore, you really shouldn’t even bother [with this option], and you could try other nonsteroidal treatments like apalutamide.

That’s not really been well studied, so potentially you would have some benefit [with] apalutamide after enzalutamide. But generally, we would recommend either docetaxel, cabazitaxel, or radium, or if you find an MSI defect or a DNA defect, then you go down that path.

VOGELZANG: I’ve had a few [patients] tell me that they’re nervous about the toxicities, cabazitaxel being a dose that’s at 25 mg/m² and you have to give it with G-CSF [granulocyte colony-stimulating factor].⁵ I don’t use that dose, I used 20 mg/m² and generally don’t give G-CSF, and…I’ve heard of that being a negative. The other thing that some [individuals] have said is, “How can it be that abiraterone and enzalutamide cause increased risk of death?”

I think it’s just a coding issue that there were [patients who] progressed rapidly. The reality is…this is very concordant with what other data show, namely that when you go to a second AR inhibitor agent, you don’t get much value from it. Therefore, your disease can be rather explosive. So those are some of the things I’ve heard in my conferences with a lot of treating doctors about this trial.

MALIK: I start out with 25 mg/m² and see how things go. I don’t necessarily start with a G-CSF, but it depends on the patient. It depends upon their performance status [and other risk factors] that are going on in terms of laboratory abnormalities. I don’t necessarily start at a lower dosage, and yes, I have seen problems with neutropenia, but once you add G-CSF, or you reduce the dose, it’s better tolerated. However, should I be reducing the dose to start with? I haven’t done that.

AMBIKA: I usually start with 20 mg/m². I think there were some studies saying 25 mg/m2 and 20 mg/m2 are tolerant when it comes to the outcome.

Depending on their age, I don’t usually start the G-CSF in the first cycle, and if they have neutropenia, we do that. For the CARD trial [NCT02485691], did all the patients get docetaxel before, or were there patients who never got docetaxel?

SRINIVAS: There was a large fraction of patients who didn’t get docetaxel, so it wasn’t all patients who uniformly had prior exposure.

AMBIKA: I have a bunch of patients who end up starting docetaxel. They don’t respond at all after 3 or 4 cycles and have bad biological disease, and then I try cabazitaxel and it doesn’t work, either. That has been my experience recently. I do have a rationale [for] patients like that, and then I must send them for trials and hopefully they will get approved at some point.

MUKHERJEE: [These are] very good data, but I generally started with the [docetaxel], but then again, patients generally tolerate cabazitaxel very well, too. I do start out with a low dose of 20 mg/m2 and I don’t add the growth factors until the patients need it, which is maybe a cycle or 2 down the road. Eventually they do, but I have found that either before [docetaxel] or after I generally sequence in cabazitaxel.

SIBLEY: I tend to follow my patients on chemotherapy closely, and just to recap, I also start people on 20 mg for cabazitaxel just to start and rapidly escalate [their treatment].

My big concern, of course, is with the infection risk… nausea, vomiting, the other issues with tolerance. I tend to follow them every other week just to make sure nothing else comes up or happens.

_REFERENCES:

_{1. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide vs bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016;17(2):153-163. doi:10.1016/S1470-2045(15)00518-5}

_{2. Messina C, Cattrini C, Soldato D, et al. BRCA mutations in prostate cancer: prognostic and predictive implications. J Oncol. 2020;2020:4986365. doi:10.1155/2020/4986365}

_{3. Rouyer M, Oudard S, Joly F, et al; FUJI Investigators. Overall and progression-free survival with cabazitaxel in metastatic castration-resistant prostate cancer in routine clinical practice: the FUJI cohort. Br J Cancer. 2019;121(12):1001-1008. doi:10.1038/s41416-019-0611-6}

_{4. Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20(12):1730-1739. doi:10.1016/S1470-2045(19)30688-6}

_{5. Fizazi K, Kramer G, Eymard JC, et al. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel vs abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study. Lancet Oncol. 2020;21(11):1513-1525. doi:10.1016/S1470-2045(20)30449-6}