Roundtable Discussion: Oh and Participants Compare Second- and Third-Line Treatments for mCRPC

William Oh, MD

William Oh, MD, clinical professor of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, lead a Case-Based Roundtable event during which physicians discussed the case of a 75-year-old patient with metastatic castration-resistant prostate cancer.

OH: Do you agree with the patient’s management to date? Would you recommend 18 months of ADT for patients?

ZHU: For the ADT, I [would recommend it for] at least 2 years, instead of just 18 months.

OH: He had some high-risk features. I think it remains an open question. There was a Canadian study that looked at 1.5 years vs 3 years, so I think that is where the 18 months came from.1 We know that this patient progressed within a short time anyway.

OH: Would you recommend an osteoclast-targeting agent in a patient like this who has metastatic castration-resistant prostate cancer [mCRPC] with 2 bone lesions and 1 pelvic lymph node?

LAMBA: Yes. We’re using [zoledronic acid and denosumab (Xgeva)].

MO: Yes. We use denosumab.

OH: Do you often send these patients for dental clearance beforehand?

MO: Yes. We always do. You don’t want them to get jaw necrosis.

OH: Do the number of bone lesions affect your decision? Is there somebody who wouldn’t use denosumab or zoledronic acid in this patient because they had only 2 bone lesions?

BRAUNSTEIN: No. I would use it, but I think it also depends on his kidney function. I’d be more likely to use denosumab. With his bone disease, I would give a bone modifying agent.

OH: Yes. The other hint, always, is that these patients, maybe unlike other patients, will always get worsening osteoporosis. So, there is a 2-for-1 benefit of starting a bone-targeted therapy.

OH: It looks like there’s pretty strong consensus on abiraterone [Zytiga] as a first choice; about a quarter of you would consider chemotherapy, which I think is certainly reasonable; a few are using enzalutamide [Xtandi]. No fans of sipuleucel-T [Provenge]; it’s a bit of a hassle, it’s a very controversial treatment. This patient would be a candidate. He is minimally symptomatic, but I think we all recognize that it would be a treatment that wouldn’t give him a lot of benefit relative to abiraterone or docetaxel [Taxotere]. Most of us consider radium 233 [Xofigo] to be a second-or third-line consideration, not a first line.

I would be curious to hear who chose chemotherapy in this patient. Who chose docetaxel and what’s your considerations for docetaxel?

BRAUNSTEIN: I would give docetaxel. He doesn’t have a high degree of visceral disease, but if he’s symptomatic and has lymph node involvement as well, I thought it might be reasonable to give him chemotherapy first.

LAU: Yes, I would give chemotherapy too because this gentleman is relatively young and healthy, had such a short period of disease control with the prior regimen, and has a Gleason score of 8. It is best for him to get the advantage of 6 cycles of docetaxel and afterwards, they can continue to androgen receptor [AR]-targeted therapy and the ADT.

OH: So, a couple of things there. First is the idea of getting the treatment in because it is high-grade cancer and second is the possibility of adding another therapy line afterwards. I’ve heard that rationale from others as well, and it certainly is a reasonable consideration.

ZHU: I am thinking of the John Hopkins AR-V7 [androgen receptor splice variant-7] assay test. The Memorial Sloan Kettering Cancer Center published a paper that validated the use of AR-V7 as a biomarker.2 I don’t know why we have not used it. Based on the circulating tumor cell results, I think AR-V7 could be the potential biomarker especially in someone who developed resistance after only 6 months on ADT.

OH: I don’t usually order the AR-V7 test because it’s easier to just do the treatment and see if it works and also because the AR-V7 test is not always reliable. It’s been very well studied and there’s a commercial test available. In patients who have not been treated yet with a first-line AR-targeted therapy like abiraterone or enzalutamide, the positivity rate is very low. So, even though you might expect that this patient is relatively androgen resistant, he probably has a high chance of responding to abiraterone although we would presume that maybe it would be for a shorter period than somebody who had not responded to primary ADT for a longer period.

The AR-targeted therapy vs chemotherapy question has never been looked at carefully. There are certainly no direct studies, but there’s some ongoing studies based of the idea of doing them in sequence. There is an [upcoming] study with darolutamide [Nubeqa] where everyone will get chemotherapy and then they’ll be randomized to get darolutamide vs no darolutamide. That will be the first study that asks the question of synergy. Maybe it should be chemotherapy plus an AR-targeted therapy, but that’s also going to add more toxicity.

MALIK: How would you choose between abiraterone and enzalutamide? In the past, it was thought that if you use abiraterone first, you’re going to always use enzalutamide later. So, other than any comorbid conditions of the patient, which are pretty much straightforward here, how would you opt for what do to? Is it based on the use of steroids with abiraterone?

OH: Yes. That’s a very good question. First, I think the evidence that enzalutamide works better after abiraterone than vice versa is still weak, unfortunately. In the mCRPC setting, there’s quite a lot of evidence that a second AR-targeted therapy is not particularly valuable. The cost issue is very important now because abiraterone is generic and there are data that show if abiraterone is taken with food, you can potentially give a much lower dose. One could prescribe one-fourth of the dose of abiraterone, which is 250 mg, with food and the pharmacokinetics would be comparable with [1000 mg of] abiraterone on an empty stomach. So, the cost issue if a patient can’t afford enzalutamide can be significantly in favor of abiraterone.

In terms of efficacy, there’s no direct comparisons between abiraterone and enzalutamide in the mCRPC first-line therapy setting. Most studies have suggested that [choice should be] based on the adverse events [AEs] profile. So, I think more people feel comfortable with abiraterone. There are differences between the different AR-targeted therapies. Enzalutamide is a little more potent, but also causes more weakness and fatigue, whereas abiraterone requires prednisone, which is contraindicated in some patients and causes some liver dysfunction.

So, those are the things that I balance in my practice. I tend to use more abiraterone than enzalutamide as first-line therapy, but I think that in this setting, either would be perfectly reasonable.

LAU: When is a good time to get a patient on sipuleucel-T? It’s not easily attainable and I have to refer it out. I once thought I had a perfect candidate, but when I referred the patient, they said the patient was asymptomatic and nothing should be done. Can you give me a textbook example of a good time to give sipuleucel-T?

OH: Generally speaking, sipuleucel-T should be the first thing you do in most patients whose cancers are rising relatively slowly but are asymptomatic rather than minimally symptomatic. In patients who are younger, you want to give them every advantage. So, I use sipuleucel-T in that setting. You can order sipuleucel-T and abiraterone at the same time and there’s data that you can give them safely simultaneously and sipuleucel-T only takes 5 weeks. There are patients who will fight back because they don’t like it. It’s too much trouble for them. I explain to them that it’s been proven time and again to have a survival benefit without necessarily making their PSA go down or showing any clinical response.

There is a paper coming out from Mount Sinai, where about 40 patients who got sipuleucel-T were studied. There are patients who have an immune system that benefits more from it and others that don’t benefit from much. The problem is there is no test yet to determine who would benefit and who would not. Immune profiling was done on those 40 patients and there were those who had very dramatic benefits if they had the right kind of T-cells at baseline.

I know that’s not particularly helpful because we can’t run that test yet, but it means there are people who have a very dramatic benefit from drugs like sipuleucel-T. Give it early on to patients with good [ECOG] performance status who are not ready to get anything else.

LAU: That was exactly my patient, except when I sent him to the institution with sipuleucel-T, they did not do anything because he’s asymptomatic.

OH: Yes. Some hospitals do not like sipuleucel-T, but there are data and guidelines on this. I always think of what I would want for my own family. What are the downsides, honestly?

There are more and more data coming out about it. Also, there are data that African Americans respond better to sipuleucel-T than Caucasian Americans. We’re used to seeing situations where African Americans do worse than Caucasians and other races, but in this case, they seem to have an enhanced benefit from it.3

This is a patient who’s already received 2 lines of therapy. So, what we’re really talking about is third-line therapy. According to the NCCN [National Comprehensive Cancer Network] guidelines cabazitaxel [Jevtana] and a docetaxel rechallenge are preferred regimens. Olaparib [Lynparza], cabazitaxel plus carboplatin [Paraplatin], pembrolizumab [Keytruda] if they have an MSI-H [microsatellite instability–high] tumor, mitoxantrone [Novantrone], radium 223 dichloride, and rucaparib [Rubraca] [are useful in certain circumstances].4,5

LAMBA: I don’t think there is a 1 size fits all, especially in the third-line setting. We’ve done it all: cabazitaxel, radium 223, hormonal therapy, and I’ve had 1 of our patients go for sipuleucel-T plus another therapy afterward because they were just the right candidate for it.

I’ve been checking for MSI-H prostate cancer all along but haven’t found it yet. We’re starting to test them right at or after first-line like most other metastatic cancers, just to have the data. So, it’s very individualized, I don’t know if there’s 1 right answer here.

OH: I think that’s a very good summary of the situation. This is what drives a lot of people crazy about prostate cancer, especially companies trying to understand why people make certain sequencing decisions about treatment. These patients have a lot of heterogeneity in comorbidity; they’re older; we have a lot of experience with what they’ve received before, and what they tolerated or didn’t tolerate. Using second-line hormonal therapy is always inferior to the experimental therapy, whether it’s a PARP inhibitor, or another chemotherapy like cabazitaxel.6,7

We only use second-line hormonal therapy because there are clinical situations where neither cabazitaxel nor a PARP inhibitor are appropriate next choices for a specific patient.

LAMBA: Is anybody still using ketoconazole [Nizoral] and hydrocortisone?

OH: Well, I used a ton of ketoconazole. I wrote multiple papers about that drug and I’ve seen some terrific responses, but it’s [tough on patients] and I don’t use it anymore. The same with estrogen, which I’ve written papers on too. High-dose estrogen has some activity, but I have not used that recently.

LAMBA: I have 1 patient on [ketoconazole] right now who’s just progressed, so that’s why I asked.

OH: I used to get calls from the pharmacy saying, “How much ketoconazole? How bad is this patient’s fungus that you’re giving such a high dose?”

OH: What is your general impression of tolerability of cabazitaxel vs docetaxel?

WU: Usually, if a patient doesn’t tolerate docetaxel, it’s very unusual for them to tolerate cabazitaxel. One of the genitourinary poster presentations showed that patients who respond to cabazitaxel well are patients who will tolerate docetaxel for at least 6 to 8 cycles. So, I usually don’t want to use cabazitaxel after docetaxel, but sometimes I don’t have any choices and I may try it.

OH: So your general feeling is if they didn’t tolerate docetaxel, that you wouldn’t challenge with cabazitaxel. Any other thoughts about tolerability of docetaxel vs cabazitaxel?

ZHU: The AEs of docetaxel are more of fluid retention and for cabazitaxel it is usually myelosuppression and fatigue. So AEs overlap, but are not completely the same. So, if your patient did not tolerate docetaxel, you could challenge with cabazitaxel.

OH: Right. Cabazitaxel causes less hair loss too. We tend to have a bias that men don’t care about hair loss, but men do care a lot about hair loss. There is less alopecia with cabazitaxel. Both cabazitaxel and docetaxel cause a lot of similar symptoms for the most part and tolerability is not the main reason we would challenge with one vs the other.

OH: Do you have patients fit for chemotherapy who are asking for an alternative treatment option perhaps due to COVID-19 concerns?

BRAUNSTEIN: I think patients who had neuropathy, substantial myelosuppression, or poor performance status are more hesitant.

MO: From March 2020, we have given a lot less chemotherapy, but now, most of the patients have come back to normal.

WU: Yes. I agree. My practice is back to normal too in terms of chemotherapy use. Patients are getting vaccinated, so it’s easier for them to accept chemotherapy now.

LAMBA: I’m a general community oncologist, so my use of chemotherapy went down during the COVID-19 pandemic mainly because there were fewer new diagnoses. All patients that were already on chemotherapy continued to stay on chemotherapy. Now that new patients are coming in, I’m not making any changes in my recommendations based on the pandemic.

OH: Are the patient volumes back in your practices? Are they higher, or are they lower, than what they were prepandemic?

LAMBA: We are pretty much where we were, maybe even a little higher.

WU: Our volume is not back to 100%. It’s close to it, but not yet. Our chemotherapy infusion volume has increased dramatically. I think it really has to do with the fact that a lot more patients are now accepting intravenous injectable therapy than oral compared with last year.

_REFERENCES:

_{1. Nabid A, Carrier N, Martin AG, et al. Duration of androgen deprivation therapy in high-risk prostate cancer: a randomized phase III trial. Eur Urol. 2018;74(4):432- 441. doi:10.1016/j.eururo.2018.06.018}

_{2. Scher HI, Graf RP, Schreiber NA, et al. Assessment of the validity of nuclear-localized androgen receptor splice variant 7 in circulating tumor cells as a predictive biomarker for castration-resistant prostate cancer. JAMA Oncol. 2018;4(9):1179- 1186. doi:10.1001/jamaoncol.2018.1621}

_{3. Sartor O, Armstrong AJ, Ahaghotu C, et al. Survival of African-American and Caucasian men after sipuleucel-T immunotherapy: outcomes from the PROCEED registry. Prostate Cancer. Prostatic Dis. 2020;23(3):517-526. doi:10.1038/ s41391-020-0213-7}

_{4. Lowrance WT, Breau RH, Chou R, et al. Advanced prostate cancer: AUA/ ASTRO/SUO guideline part I. J Urol. 2021;205(1):14-21. doi:10.1097/ JU.0000000000001375}

_{5. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer guidelines, v2.2021. Accessed August 5, 2021. https://bit.ly/3xFf363}

_{6. de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel vs abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206}

_{7. 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}