During a Targeted Oncology Case-Based Roundtable event, Matthew Smith, MD, PhD, discussed genomic testing in prostate cancer with a group of peers.
During a Targeted Oncology Case-Based Roundtable event, Matthew Smith, MD, PhD Claire and John Bertucci Endowed Chair in Genitourinary Cancers Professor of Medicine, Harvard Medical School Director, Genitourinary Malignancies Program, discussed genomic testing in prostate cancer with a group of peers.
MATTHEW SMITH, MD, PHD: In a textbook example of [a patient with] nonmetastatic castration-resistant prostate cancer [nmCRPC], is there a role for hereditary germline testing in this patient?
TAMI BACH, MD: I think there’s always a role for hereditary germline testing. The question is: “When do we do anything with it and what to do?” I think I usually germline test these patients right now for potential use of PARP inhibition later. But I don’t think I would use [the PARP inhibitor] up front.
SMITH: That’s fair. For which patients do you routinely offer germline genetic testing? Is it just the patients with de novo metastatic disease or is it more like the NCCN [National Comprehensive Cancer Network] guidelines, which are very broad?
BACH: I guess when I get these patients, it’s with metastatic disease, so I’m usually testing them at that point. I probably am not testing them earlier. I would have to pull up NCCN and see what NCCN recommends. But I think it’s based on treatment algorithm and where I am in the paradigm as far as treatment goes, and what I can use. If there is hereditary cancer, I would probably start the [genetic testing] a bit earlier. I think as far as treatment-related testing, it would be later, and it would be in patients who are metastatic, whether or not they’re de novo; I’m not sure whether that would make a difference to me.
SMITH: I think that’s fair. The NCCN guidelines are surprisingly broad. They pretty much would consider germline testing for anyone with a Gleason [score of] 7 or higher, particularly in that group with [patients who] have a family history.1 But I think your points are spot-on. Certainly, prioritize germline genetic testing for patients with metastatic disease and patients without detectable metastases who have a family history, or younger patients.
GABOR VARADI, MD: In the past we didn’t really send [out for testing]. But nowadays, mainly, if there is a strong family history, then we do germline testing.
SMITH: Do you routinely collect [information on] the family history? Do you do that on your own? Do you refer patients for genetic counseling and testing?
VARADI: First I do, and then we’re referring more and more to a genetic counselor.
SMITH: Same here. Would you do additional imaging on [such a] patient? [Do you] recommend other imaging—fluciclovine PET is deemed to be relatively broadly available, PSMA PET is coming but not broadly available.
DAVID MINTZER, MD: It probably won’t make any difference. But if you believe you might find a solitary site of disease that can be amenable to radiosurgery and if you believe that’s going to increase his overall survival [OS], I suppose you can get it. It seems to be an increasing trend, although [I’m] not certain it’s proven yet.
WILLIAM ROSS GREEN, MD: I agree. I’d probably look for fluciclovine PET or PSMA if we have it. If it’s oligometastatic, I think I’d give them the benefit of the doubt and try to treat aggressively.
SMITH: I think that’s fair. When we did the nmCRPC studies, there was no requirement for postoperative radiation therapy for entry. With follow-up on those trials, we did identify patients whose sole site of progression was a local recurrence. That is, I think, worth considering in patients who haven’t had salvage local therapy—at least to consider that as a possibility.
SMITH: What are the practical implications of these [trial] data in your practice? Did the later observation of an improvement in OS change your thinking about the evidence in this setting?
BORIS KOBRINSKY, MD: [Each trial includes the addition of] ADT [androgen deprivation therapy], but what was ADT in this setting? Was it just a GnRH [gonadotropin-releasing hormone] agonist, like Casodex [bicalutamide], which is a first-generation antiandrogen?
SMITH: ADT was a GnRH agonist or antagonist or, in rare cases, [that a patient received] bilateral orchiectomies. So patients in this trial were not receiving a firstgeneration antiandrogen. They had to have discontinued it before they enrolled in the trial. They could have received it in the past.
KOBRINSKY: I got it. So we don’t know whether this second generation is better than first generation, then?
SMITH: Not from these 3 trials. That question was asked in a study done mostly in Europe comparing enzalutamide in a randomized phase 2 to bicalutamide.2 There’s an enormous difference in the outcomes. They were not large enough to look at OS, but they looked at things like PSA [prostate-specific antigen] response [and progression-free survival (PFS)]. There was a dramatic difference between enzalutamide and the first-generation antiandrogen. It was a large, randomized phase 2 trial. It’s not the size of the 3 trials I’m referring to here, 1200 patients, but it was in the several-hundred-patient category.
KOBRINSKY: Is there any trial showing that [in using a] GnRH [agonist] plus a second-generation [hormonal therapy] versus doing the same thing with the first generation, that the second generation is better?
SMITH: Not specifically. But I think the best we have is this randomized phase 2 trial. It’s also worth noting that first-generation antiandrogens were allowed [in these 3 trials of the second-generation agents]. In the original publications they described the percentage of patients; if I recall correctly, about one-third had received a prior first-generation [antiandrogen].
KOBRINSKY: So why do you think the trial designers did not choose [first-generation antiandrogens] as a standard- [of-care comparator]? Why did they choose to use a single GnRH agonist versus the same plus second generation? It would be logical to assume that this is a current standard of care now. We want to advance the standard of care going against the old standard of care. Why [not then] use just a GnRH that is clearly inferior?
SMITH: It’s a really interesting historical debate, but I think there are a couple of points [here]. One is that the question you’re asking is: “Is combined androgen blockade more effective than GnRH agonist or antagonist monotherapies?” This is one of the most-studied questions in prostate cancer. The overarching conclusion is that there is little or no difference. I would refute the idea that combined androgen blockade is the standard of care or, for that matter, that adding bicalutamide or flutamide is any standard of care for patients with CRPC. It’s never been shown to improve [outcomes].
Although you have occasional, usually transient, PSA responses, there’s never been an improvement in any important clinical outcome, PFS or OS. Then the second point is that the question you raised has been studied in a randomized, large phase 2 trial that showed unequivocally that, as you might expect, the more potent antiandrogens were more effective by all measured criteria.
[Also], I think the reason that they weren’t included [was that] these were global trials. In much of the world, and certainly in my practice, I wouldn’t consider adding bicalutamide or flutamide as the alternative standard of care because they’ve never been shown to improve clinical outcomes, although I’ll acknowledge they were commonly done in the past.
DANIEL EKAHA, MD: When these 3 [trials showed] the data for metastasis-free survival, we all scratched our heads a bit and said, “You know, prior to this, we were observing these patients; is there going to be an OS benefit?” Then we see an OS benefit, which does influence use of these drugs. So then you find the PSMA [prostate-specific membrane antigen], and I see 1 or 2 or 3 other burden metastases. Am I going to do anything differently? No.
So I’m saying, “No, I’m OK with just my bone scan now.” Because I’m going to use those drugs anyway in these patients who are progressing. If they haven’t gotten pelvic radiation therapy, and I think that they probably have oligometastatic disease, I may still offer them salvage radiation at some point. So [I’m maybe less inclined], in these kinds of situations [of a] technetium bone scan–negative patient, to try to push for a PSMA because I’m probably going to be doing the same thing that I’ll be doing without one.
SMITH: I see clinical practice the same way. These patients who are bone scan and CT negative but PSMA-PET positive [are who are] best applied to metastatic disease; they’re the exact patients who were studied in these 3 pivotal trials. No such patients were included in the earlier trials in the so-called mCRPC [setting]. So it is a bit of a reclassification point. There have been PSMA-PET studies that have looked, basically, at a simulated population, like SPARTAN [NCT01946204], PROSPER [NCT02003924], and ARAMIS [NCT02200614]. Most of them have detectable metastatic disease by PSMA PET. So I guess that shouldn’t come as a surprise given the extreme sensitivity of that imaging modality.
SMITH: Do you have experience with using these agents, and if so, has your experience been consistent with the trials?
MICHAEL ROTKOWITZ, MD: I [am] more familiar with the seizure correlation with enzalutamide—the STAMPEDE trial [NCT00268476]; [abiraterone acetate (Zytiga) has] been around longer—I have used that in my practice. I sometimes use some prophylactic steroid or antihistamine for the rash. But I find it to be pretty well tolerated, and patients are able to stay on the treatment. I’ve been an early adopter, and I’ve really implemented it into the practice with good success. The question always is: “Is it the natural biology of the disease or is it really the intervention that’s affecting the true direction?” But I think that the data, especially the updated ASCO 2020 [2020 American Society of Clinical Oncology Virtual Scientific Program] OS data, really behoove you to act and be preemptive.
SMITH: I could say it’s gratifying to see that. When we designed these trials, most of us, even the most ardent supporters of the trials, were far from certain that this would translate into a survival benefit. Because the thinking was that all the subsequent therapies that would occur would overcome any potential survival advantage of early intervention. It’s been presented, for each of the drugs, that there was a lot of subsequent therapy. As in SPARTAN, that OS benefit seen [73.9 months with apalutamide vs 59.9 months with placebo; HR, 0.78; 95% CI, 0.64-0.96; P = .0161] was despite the fact that the vast majority of patients in the placebo group got other lifeprolonging therapy.3 This wasn’t like early apalutamide versus no treatment in the control group.
A lot of the patients received, promptly, other AR [androgen receptor] therapy at progression. In fact, in that study, we provided abiraterone for free to patients at progression to encourage, basically, retention in the trial. But despite giving that early salvage therapy for nmCRPC, there was this survival benefit. The other part was that when the study was unblinded for the MFS [metastasis-free survival] benefit, all the patients in the placebo group were free to cross over to apalutamide. So there was a lot of subsequent therapy, and that survival benefit really was seen despite all that. So, I think it does translate into a practice where you’d be intensive with intervention.
HAYMAN SALIB, MD: Among the 3 [newer AR inhibitors]— apalutamide, enzalutamide, and darolutamide—from your experience, [what is] the degree of water retention? I have a patient who I put on enzalutamide and they developed a lot of water retention in their lower extremities. Is this [something] you see [often?] I didn’t realize it can happen that much. [Or is it that I gave] too much and we have to hold the medicine [or cut] the dose? Have you seen water retention [in the] lower extremity among the 3, and what you do about that?
SMITH: I don’t believe that’s a well-recognized adverse effect [AE] of any of the 3 agents, including enzalutamide. With abiraterone, it’s certainly a big issue. Different mechanism of action. Fluid retention is a well-known AE of abiraterone. I’ve seen some horrors of patients; for example, snowbirds who went off to Florida, who came back with massive peripheral edema. It was an unrecognized AE of their abiraterone, which was started there, as an example. But it is not a known AE of enzalutamide, to the best of my knowledge. But I would certainly be concerned; it certainly sounds like an AE in that patient.
SALIB: That’s what I suspected. It is listed as an AE. But in the clinic, I didn’t see it very often. But [there] happened to be 1 patient who has bad lower extremity edema and we blame the medicine.
SALIB: I send for genetic testing because I’m in private practice, so I take the liberty to test my patients from the beginning. So I send for Invitae to look into that. I send for the liquid biopsy, as well, and if it’s related to a different cancer or some genetics, that could be useful in the future. So I test every patient with first cancer and I have no restrictions on my end. The testing is very cheap and very acceptable to the patient.
SMITH: What are your preferred platforms for testing? Are you doing germline genetic testing or tumor genetic testing or both?
SALIB: I do both of them. I do peripheral and the germline. I do the testing on the specimen if I can and the blood, as well.
SMITH: Do you routinely order or recommend patients have genetic testing with prostate cancer?
KOBRINSKY: No, I don’t think there are good data right now to change management. I do it only in patients who I suspect may have, again, a family history or some other situation where I think it’s highly possible. In terms of sending the tests, I want it neutral because it’s still possible. But [there are] still a lot of strings attached, insurance issues, efficiency—all this needs to be better. So it’s still not a free ride in terms of doing it easily.
SMITH: You said that you focus primarily on the patients who have a strong family history. I certainly would endorse prioritizing those patients, because arguably, that’s where the money is, where you’re going to find patients. I’ve been practicing for long enough to now have multiple generations of patients with prostate cancer, some of whom are related by their BRCA mutations, for example. It’s a humbling part of the practice.
But interestingly enough, in the University of Washington paper in the New England Journal of Medicine that described this relatively high rate of germline DNA repair defects in patients with metastatic prostate cancer, family history did not predict a positive result.4 Now, it may be that they were focusing in their interviews on prostate cancer and they weren’t doing structured interviews to look for breast and ovarian cancer, because they didn’t yet know the results of their study. But I have to say, I prioritize patients with a positive family history, but I certainly wouldn’t exclude patients with no family history. I’d say probably half of the patients we’ve identified are founders, meaning that they were not previously known to have a germline mutation in the family.
EKAHA: I agree. I test our germline, but I also do tumor testing when I can. Again, we have [treatment] implications with the PARP inhibitors in the patients who have a DNA repair deficiency. The question, though, is that we see in ovarian cancer that you can have somatic mutation almost as frequently as a germline mutation. What’s the frequency of somatic mutations in the absence of germline mutations in prostate cancer?
SMITH: We don’t know with certainty. But it would appear that if you look at all patients with mCRPC who have pathogenic mutations, about half are germline.
Now, the other, harder part to answer about that is that my impression is that it’s really the ones with germline mutations that are uniformly the driver mutations. So, if you have a BRCA2 germline mutation, I have no doubt it’s a driver mutation in your cancer. If you have a somatic ATM mutation, maybe not. It’s probably less predictive of benefit from a PARP inhibitor.
But the way we do it in practice—and I wouldn’t say this is right or wrong, it’s just what we generally do— is we do germline testing in everybody with metastatic disease. That’s binary, of course; either you’re born with it or not. Then we tend to save the more expensive tests for later, in part because those results are not going to be actionable until later. Then, although it’s not really clear that they accumulate those mutations, we think that the DNA repair deficiency mutations are relatively early somatic events. So [there’s] probably no harm in doing it earlier.
1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2021. Accessed March 23, 2021. https://bit.ly/3d8ZR8X
2. Siemens DR, Klotz L, Heidenreich A, et al. Efficacy and safety of enzalutamide vs bicalutamide in younger and older patients with metastatic castration resistant prostate cancer in the TERRAIN trial. J Urol. 2018;199(1):147-154. doi:10.1016/j. juro.2017.08.080
3. Small EJ, Saad F, Chowdhury S, et al. Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;38(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516
4. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144