Roundtable Discussion: Therapeutic Sequencing for Metastatic Castration-Resistant Prostate Cancer

Ulka N. Vaishampayan, MBBS

During a Targeted Oncology Case-Based Roundtable event, Ulka N. Vaishampayan, MBBS, professor of Medicine and professor of Oncology at Mayo Clinic and Joshua M. Lang, MD, MS associate professor, Medicine and vice chair, Biomedical Research at University of Wisconsin Carbone Cancer Center, discussed the case a 75-year-old man with metastatic castration-resistant prostate cancer.

TEJWANI: I agree with surgery or radiation, and additional ADT is the way to go. I don’t know if he was offered surgery. We do give them the option of radical prostatectomy, unless it is very high-risk disease, tumor outside the prostate gland, lymph nodes involved, etc.

VAISHAMPAYAN: So typically, you would approach a PSA of 32 ng/mL with radical prostatectomy?

TEJWANI: Yes. They do an MRI of the pelvis. If there are no lymph nodes involved, if there is no tumor outside, then the patient meets with the urologist and the urologist decides.

VAISHAMPAYAN: I agree with your comment about getting additional staging if you are considering something like surgery.

HADDAD: I have a comment on bisphosphonates. I recognize there is no substantial evidence for using bisphosphonates in castration-sensitive disease, but with the patients being on ADT therapy for probably the rest of their life, I don’t want them to end up with osteoporosis, especially many of those [who are] older. So I put them on some form of bisphosphonate, but not frequently. Maybe every 3 or 6 months, depending on the case. I’m not sure if this is common.

TEJWANI: I usually do bone density [testing] in anybody who is [on therapy for] more than 6 months. If they have osteoporosis or osteopenia, I would use it. But if their bone health is normal, then I follow [their test results].

Joshua M. Lang, MD, MS

LANG: It makes a lot of sense, especially when you have patients over the age of 65, to consider getting a bone density scan. As Dr. Haddad mentioned, ADT can accelerate bone mineral density loss to up to 5% per year. It doesn’t happen for everybody, but it’s certainly worth evaluating and considering, especially for somebody who’s 75.

TEJWANI: If their bone density is normal, would you offer them bisphosphonates?

LANG: Personally, I would not offer bisphosphonates. I think that’s a great time to recommend exercise to help mediate some of the adverse events of ADT. Being able to avoid an extra medication—I think most of my patients appreciate that.

VAISHAMPAYAN: I must say that with the fracture data, though, it’s getting easier for me to prescribe the bone health agents. I [prescribe] denosumab [Prolia] once every 6 months to once a year, but that is something to consider, to prevent bone loss rather than waiting until it happens— proactive management. I think it is not written in stone by any means, and for the younger patient it may not be necessary, but in someone who’s older, that might be something to consider, also if they have risk factors for osteoporosis, smoking, etc.

Anyone else have thoughts about whether to do specialized scans up front on these patients? At the diagnosis, fluciclovine [Axumin] scans are not approved as of now for that setting.

HADDAD: [With] the rising PSA, you cannot see disease, but you highly suspect there is disease, right?

VAISHAMPAYAN: Right. Those specialized scans are not available for an up-front diagnostic case, as of now, at least from [the perspective of] FDA approval.

RICH: Had [clinicians] done advanced imaging on this patient up front and found that that right hip pain maybe was low-volume metastatic disease, do you think that would abrogate the need to provide local therapy and [could have] saved him radiotherapy or surgery?

VAISHAMPAYAN: That is going to become more and more of a treatment dilemma, as in centers such as ours, where we have PSMA [prostate-specific membrane antigen] scans available. So, I agree with you.

AL BAGHDADI: I regularly image those patients. It’s not a covered test, but we regularly get it. Ultimately, if it lights up, we start with combination hormonal therapy in patients such as this and defer radiation. The decision in the beginning is to defer. [If] there’s a trial, we might put them on a trial for local radiation or resection 6 months later….We start with hormonal therapy and see how it goes.

VAISHAMPAYAN: Yes, I agree. There are no data to show that doing local therapy with an early diagnosis of metastatic disease improves survival, though studies are right now being conducted. So the imaging, frankly, is way ahead of us actually doing the clinical trials looking for patient outcomes, which is going to take years of follow-up.

FRONTIERA: I was surprised that they were so aggressive in regard to his initial [treatment]. His PSA was 32 ng/mL, and my teaching has always been, if you have a PSA of 32 ng/mL, you have metastatic disease, you just haven’t found it. And if he has a symptom, I think you need to look at that further. I guess I would have probably done an MRI of that hip to try to help clarify that.

VAISHAMPAYAN: Would you have radiated the prostate?

FRONTIERA: No, not with a PSA of 32 ng/mL if we identified metastatic disease. And my suspicion of metastatic disease would have been very high.

TEJWANI: I just wanted to make a point that for castration-sensitive metastatic disease, we are enrolling on SWOG 1802 [NCT03678025] to answer the question of whether local therapy should be done.

VAISHAMPAYAN: You bring up an excellent point; there are studies ongoing.

BARAI: I had a patient with very high PSA, almost 280 ng/mL. We couldn’t find any metastatic disease. The prostate was significantly enlarged. [The patient went to Mayo Clinic, where doctors] thought that it was the prostate that was the source of the high PSA. Can you comment on that?

VAISHAMPAYAN: I have occasionally seen cases even with PSAs of 150 or 180 ng/mL without cancer, just from severe benign prostatic hyperplasia or [something such as that]. But those are more the exception. I think [with a PSA level of 200 ng/mL and an enlarged prostate], though, local therapy might become important even for the symptoms of the patient. So, absolutely, start with systemic therapy there, and then, depending on the response, consider the patient for local therapy.

LANG: I completely agree. I think, unfortunately, because we’re seeing this increasing incidence of men presenting with metastatic disease, whether that’s the decline in PSA screening or other factors, intact local primaries that are progressing can be horribly symptomatic: urinary obstruction, pelvic pain, pelvic discomfort. And the role for treating the primary site, especially in patients who have great responses, can be very useful in terms of improving quality of life.

VAISHAMPAYAN: [More than one-fourth] of you want abiraterone [Zytiga] and the majority picked enzalutamide [Xtandi]. Nobody really wants to do chemotherapy, sipuleucel-T [Provenge], or radium 223 [Xofigo]. I think one of the hormonal agents is perfectly reasonable, easy to take, etc.

TEJWANI: Sometimes we have patients [whose insurance plan] dictates that abiraterone be used first before they will approve enzalutamide. I prefer enzalutamide, mainly because you don’t have to deal with steroids—if they’re diabetic, you don’t have to regulate their blood sugars—and fewer pills to take: 4 vs 4 and prednisone together. But if he did not have pain, I would consider sipuleucel-T also. Patients with relatively asymptomatic bone metastases will qualify for the sipuleucel-T treatment. But I would reserve docetaxel [Taxotere] for high-volume disease. This patient doesn’t have any visceral or high-volume bone disease; only 3 sites were mentioned. So enzalutamide and abiraterone both will be acceptable, depending on his insurance.

RICH: To defend abiraterone: I think enzalutamide is a harder drug [to take] than most people give it credit for. We see a lot of constitutional symptoms, a lot of fatigue, a lot of dose reduction in these patients, especially older men. For [patients] who don’t have overt diabetes, who don’t have overt cardiac issues, I think abiraterone and prednisone are better tolerated. You can get away with lower doses of prednisone by titrating to hypokalemia. So, at least from our perspective, I think enzalutamide is a harder drug [to take] than darolutamide [Nubeqa] and apalutamide [Erleada], which are my first choices in alternative settings. I just have had difficult times with enzalutamide.

AL BAGHDADI: I think the efficacy is similar. The only difference is that I see enzalutamide working better after abiraterone [than] vice versa. I rarely see abiraterone working after enzalutamide failure. But with enzalutamide, the main problem is cognitive impairment, which I see...in those patients. And sometimes neuropathy, that creeps up on you. I’ve seen significant motor neuropathy with enzalutamide. We typically sit and go over the patient’s comorbidities and make a decision, whether it’s abiraterone or enzalutamide. I’d be hard pressed to use docetaxel in a 75-year-old patient, even if he has a lot of disease. I think darolutamide is the absolutely best drug out of all of them, but it’s not yet approved in this situation.

VAISHAMPAYAN: It’s not approved in castration-[sensitive] disease at all.

LANG: There’s a randomized phase 2 trial, Khalaf et al, [with results] published in Lancet Oncology in 2019 [NCT02125357].1 In patients who received abiraterone followed by enzalutamide, there was a higher PSA response rate compared with those patients who received enzalutamide followed by abiraterone, where there were almost no PSA responses. It’s a randomized phase 2 [trial], with those caveats, but it does support that you can have responses going from abiraterone to enzalutamide, but not often in the reverse.

MATTOUR: The Lancet Oncology article made me a bit more comfortable with considering abiraterone as an initial option for discussion with the patient. To me, it makes dealing with the steroids more acceptable from a practical standpoint, unless the patient [has severe diabetes] or has very poor bone density.

VAISHAMPAYAN: The National Comprehensive Cancer Network [NCCN] guidelines for patients with no prior docetaxel and no prior novel hormonal therapy [provide] options: abiraterone, docetaxel, enzalutamide, and then occasionally sipuleucel-T and radium 223 for symptomatic bone metastases.¹ Each of these is category 1, which means that there is a well-conducted, randomized trial that has shown improvement in survival outcomes.

The other recommended regimen is “other secondary hormone therapy.” There are studies clearly now showing that there are multiple agents that are better than the older AR blockers, etc.

VAISHAMPAYAN: Would you do [germline testing] up front when you first see the patient? At what stage would you do his genomic testing?

AL BAGHDADI: It depends on the history. Without a strong family history, I do it as soon as there’s metastatic disease. If there is a family history, men or women in the family with consistent diagnoses, I do it up front.

TEJWANI: Yes, I do it. For metastatic prostate cancer, NCCN guidelines say to test everybody for genetic mutation. But this patient’s disease is castration resistant, not sensitive to docetaxel, and he’s in pain, so radium 223 will be an option. [I would offer] next-generation sequencing to see if he qualifies for a PARP inhibitor; that would be an option, as well. If the tissue is available once they have metastatic disease, we do the testing from the get-go.

VAISHAMPAYAN: You prefer to do it on tissue if you can?

TEJWANI: Yes.

VAISHAMPAYAN: For germline genomic testing, the guidelines for high-risk prostate cancer—the NCCN guidelines— this patient would have qualified for right at the get-go.2 But you’re not going to do much with that, except if they have any of the germline mutations—then you would need to consider family members for counseling. But at metastatic disease, you definitely need to start thinking. So for metastatic disease, NCCN guidelines would cover every patient for you to do germline testing or somatic. Somatic testing you can do once they have metastatic disease.

VAISHAMPAYAN: How would you test for MSI [microsatellite instability] and DNA repair deficiency? For MSI, etc, you need tissue. What are you going to send?

AL BAGHDADI: Well, not necessarily. You’ll get that on liquid biopsies—Guardant360—within a week.

VAISHAMPAYAN: Is that what you are going to use?

AL BAGHDADI: [Yes,] I find myself frequently doing that.

VAISHAMPAYAN: So for patients who have metastatic prostate cancer, it’s easier to do liquid biopsy?

AL BAGHDADI: There’s evolution of the disease, and testing a prior tissue biopsy might not be representative after all these treatments. That’s been well described: that you have a higher incidence of these mutations as the disease progresses. I find myself doing liquid biopsies rather frequently with prostate cancer.

TEJWANI: Some patients had a prostatectomy 10 or 20 years ago and we may not have access to the tissue. So we have been doing a lot of liquid biopsies as well. If the tissue is available, I thought for prostate cancer the mutations don’t change much. Would you clarify that?

VAISHAMPAYAN: I think they stay pretty consistent from what we know, although there are limited data. The other problem with the liquid biopsy is that there can be some false-positive DNA repair mutations that are noted. They are from the clonal hematopoiesis that has been seen. In older patients, there is a rate as high as 20% of false positivity. Within these limitations, obviously, it’s a very convenient thing to do, to use liquid biopsy to test the patients. As long as you know these caveats, I think it’s perfectly fine to use it. It’s definitely much more convenient than bone biopsies.

TEJWANI: If the tissue is available, our preference is always to send the tissue over the liquid biopsy.

LANG: Data from the University of Washington [show] that the truncal mutations, or the driver mutations, are often common across different metastatic sites, but we can see heterogeneity in some passenger [mutations]. But occasionally we get new drivers.

The real concern is if we start to see a [TP53, RB1, or PTEN] mutation; that could indicate a potential emergence of a neuroendocrine prostate cancer. Hopefully, you would pick that up on a biopsy.

What Dr Vaishampayan said was absolutely right in terms of clonal hematopoiesis. There’s a great review by Wyatt et al essentially suggesting that when you look at your liquid biopsy reports, if they don’t do a germline test at the same time—which would pick up clonal hematopoiesis, which most of them don’t—then you need to have a variant allelic frequency at least greater than 1% and probably higher to give you more confidence in those liquid biopsy results to be accurate.3 If there’s a lower frequency, it’s much more likely to be a false positive. [There are] a lot of caveats and caution with those liquid biopsies.

VAISHAMPAYAN: Some of the institutional tests will test the leukocytes for that, but most of the commercial tests don’t.

TEJWANI: We prefer radium 223 for symptomatic patients with pain if their testing is negative.

VAISHAMPAYAN: Does the lymph node bother you with that?

TEJWANI: It does, but he’s in pain, and the radium 223 is for bone metastatic disease. I think I would first treat with radium 223, control his pain, and then reassess the disease. I have used it with bone and lymph node disease if they are very symptomatic.

VAISHAMPAYAN: And, typically, do you find that you achieve pain control with radium 223?

TEJWANI: Not all the time. I would say maybe 4 out of 10 people achieve a good pain control with radium 223. We are all waiting for the new lutetium Lu 177-dotatate [Lutathera] treatment, but it’s not available at Henry Ford [Cancer Institute].

VAISHAMPAYAN: It’s not available anywhere right now, unless it’s a clinical trial or expanded access.

HADDAD: What was the interval between docetaxel and the progression?

VAISHAMPAYAN: Three months.

HADDAD: There are recent data to support cabazitaxel [Jevtana].4-7 I would consider it if the molecular test were negative and he had tolerated docetaxel fairly well.

AL BAGHDADI: If I recall, there was a lot of lymphadenopathy, and the kinetics of the PSA—it was rapidly rising; the PSA was up to 60 ng/mL. It depends on how much disease is outside the bones, and how much the PSA increases.

But in general, I’d probably [give this patient] cabazitaxel at 20 mg for a patient like this. I don’t worry too much about the neuropathy at 20 mg, and preceding docetaxel I have not seen patients complaining of severe neuropathy.

VAISHAMPAYAN: I agree with you. Typically, there has been very low incidence of neuropathy with cabazitaxel, as compared with even docetaxel. There is a difference in the toxicity, even though it is a taxanelike agent, a tubulin inhibitor.

VAISHAMPAYAN: If you had severe neuropathy come on right at the get-go, after 2 or 3 cycles, would you have switched the patient to cabazitaxel?

TEJWANI: I have done that, but I think we see more neutropenia. Most of the patients require pegfilgrastim [Neulasta] or growth factors. I have had patients who did not tolerate docetaxel, but they did pretty good with cabazitaxel at 20 mg/m2. We have evidence, based on the trial [results], comparing cabazitaxel with the second agent abiraterone vs enzalutamide. It was better to use cabazitaxel.

VAISHAMPAYAN: AR-V7 was tested in circulating tumor cells [but it] never quite got validated and came into clinical practice. If you’re running the genomic testing on tissue, chances are it will report the AR-V7 or AR mutations. And, if they have an AR-V7 mutation, the patient’s disease is likely to be resistant to abiraterone or enzalutamide. But in this case, what would drive you toward chemotherapy over an AR–targeted agent?

HADDAD: That’s after he’s been exposed to both?

VAISHAMPAYAN: Yes, the patient got enzalutamide, followed by docetaxel.

HADDAD: How much he benefited from chemotherapy and what toxicity he ended up with, probably.

VAISHAMPAYAN: Fair enough.

_REFERENCES:

_{1. 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}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 1.2022. Accessed November 13, 2021. https://bit.ly/3Hlbw2I}

_{3. Wyatt AW, Annala M, Aggarwal R, et al. Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer. J Natl Cancer Inst. 2017;109(12):djx118. doi:10.1093/jnci/djx118}

_{4. Fizazi K, Kramer G, Eymard JC, et al. Pain response and health-related quality of life (HRQL) analysis in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel (CBZ) versus abiraterone or enzalutamide in the CARD study. J Clin Oncol. 2020;38(suppl 6):16. doi:10.1200/JCO.2020.38.6_suppl.16}

_{5. de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206}

_{6. Fizazi K, Kramer G, Eymard JC, et al. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus 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}

_{7. de Wit R, Kramer G, Eymard JC, et al. CARD: randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394}