Roundtable Discussion: Trials Demonstrate Efficacy With Different Regimens in Nonmetastatic CRPC

Targeted Oncology Staff

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Eleni Efstathiou, MD, PhD, discussed clinical trials which support the use of certain treatment regimen for patients with nonmetastatic castration-resistant prostate cancer.

During a virtual Targeted Oncology Case-Based Roundtable event, MD, PhD, associate professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, TX discussed clinical trials which support the use of certain treatment regimen for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Targeted OncologyTM: What treatments are FDA approved for the potential treatment of this patient with nmCRPC?

EFSTATHIOU: The National Comprehensive Cancer Network guidelines [divide up the treatments by] the PSA doubling time.1 When it’s less than 10 months, you get [many] options: [apalutamide (Erleada), darolutamide (Nubeqa), and enzalutamide (Xtandi)]. In fact, the [large realm of] first-generation antiandrogens, even abiraterone if nothing else is available, [are possible treatment options]. But [if the doubling time is] more than 10 months, the options are observation, which is the preferred option, [or a secondary hormone therapy].

What I would add to this case is [my suggestion to] always look at those serum levels of testosterone. I like to tie [that in] with my PSA, and I do it at the same time.

Targeted Oncology: What trials and data support the 3 treatment options in the case of a shorter PSA doubling time?

EFSTATHIOU: There are 3 trials—and this is the value, because 1 trial is like [having no] trials. If you have 3 trials that have essentially the same design and similar type of class of agent, and are conducted in the same population, that have almost identical results, well, that’s not to be challenged, I would say. If you have only 1, it’s a problem. The [design of the] phase 3 SPARTAN trial [NCT01946204] was 2:1 randomization of men with nonmetastatic therapy who could have pelvic nodes and had to have a PSA doubling time of less than 10 months.2

The nice thing about SPARTAN is that they not only [calculated] the metastasis-free survival [MFS], but they also had, as an exploratory end point, the time to second progression-free survival [PFS2]. That’s what made the difference for this trial.

The patient characteristics [account for] the typical patient who you’ll see walk in the door: excellent performance status, older median age in the trial, 74 years], may have other comorbidities.

The first year [the investigators] showed us MFS, the second year they showed us the updated MFS,3 and at the final analysis, [it was] still holding a very nice HR with a difference of 2 years, essentially, in MFS [40.5 months with apalutamide vs 16.2 months with placebo; HR, 0.28; 95% CI, 0.23-0.35; P < .0001]. In the analysis that was recently shown, [we saw] the overall survival [OS] benefit in favor of apalutamide [73.9 vs 59.9 months with placebo; HR, 0.78; 95% CI, 0.64-0.96; P = .0161].4

Of the 3 trials, this is the only one that was recording adverse events [AEs] every month; the other 2 trials were doing it every 4 months, so you can’t really compare among all of them. Just keep in mind that the AEs are in line with what we have seen in CRPC and hormonenaive disease, not something excessive. I would say that in SPARTAN, I [don’t think] we had any seizure disorders.

My experience with apalutamide is that it’s better tolerated from a fatigue perspective. However, [rash is a concern with apalutamide, seen in 24% of patients versus in 5.5% of patients treated with placebo].5 I personally have not seen rash—[really], very little. I have not had to stop [treatment in any patients], and I’ve treated many more than 100. In 1 patient, I should have remembered to look more carefully in the beginning at his allergies; he had allergies to all antibiotics. He is the only patient who I changed from apalutamide to enzalutamide, and the rash completely went away. So, something specific to apalutamide contributes to that.

The rash that has been encountered has never been to the degree of a Stevens-Johnson, ever. But in all the trials, about 9% of cases have had patients who have had to stop, so 1 of 10. [It’s notable that we] saw a higher percentage of that rash in the Asian population. What we’re not 100% sure about is whether it is related to the lower body mass index [BMI]—because BMI is at least 15% lower than in the European and North American population—or if it is a race-specific event, or a combination.

Another thing that I want to point out with apalutamide is that apalutamide has a drug-drug interaction with ciprofloxacin [Ciloxan] through increase of metabolism. Therefore, we need to be really careful, because 8% of patients may actually develop a clinical hypothyroidism. In my panel of tests, I do a thyroid-stimulating hormone test every 3 [months and give] special care for those men who are on supplemented thyroxin; quite a few are in our population.

Next, [we can discuss] the PROSPER trial [NCT02003924]; I’ll disclose that I was a coauthor of the papers that came out, [stemming] from the European side of my practice. It was similar to SPARTAN. With enzalutamide, we’re talking about an approved drug, so every-month monitoring wasn’t necessary; they went every 4 months. In this case, again, the randomization was 2:1. They did not do the PFS2, but they looked at exactly [the same things as in] the SPARTAN trial. Again, we see the same median age, [74 years].6

I want to point out something: “Baseline use of bonetargeting agents” [90% of patients had not received prior bone-targeting agents]. I’m not talking level of metastasis, but we’re talking about prevention of osteoporosis; only 10% of these men who had been on ADT for years were receiving any type of prevention, whether it was in the form of denosumab [Xgeva; Prolia] every 6 months, or zoledronic acid [Reclast], or [another agent]. This is one of the big caveats in all our practices: We need to get better at [preventing osteoporosis] and assessing patients’ bone density.

Again, we could [just about superimpose] these results with those of the SPARTAN trial. So, we get again a 0.29 HR [for MFS; 36.6 months with enzalutamide versus 14.7 months with placebo] and a 0.73 HR for OS [67.0 months versus 56.3 months, respectively].

AEs were reported a little differently for PROSPER, and I’m not sure I really, really agree with this way. I’ve had a discussion with [the investigators] regarding this. Some of you may remember that a chunk of patients who discontinued enzalutamide died relatively rapidly as compared with what was expected, and that is an issue that has not been explained fully. I would say that it points to the fact that we need to be more careful about recording cardiovascular events if they occur. This is an open discussion that we’re having with the sponsor of that trial, of course.

Which brings us to ARAMIS [NCT02200614], the newcomer. The only part that is a little bit of a, let’s say, difficulty, with darolutamide is that unlike the other drugs, it has to be given twice a day. It has to be given as 2 pills twice daily—so it’s again 4 pills, but it’s twice a day—and this can be a problem with polypharmacy with our patients. It was the same type of trial design: randomization 2:1 in men, by conventional criteria, nonmetastatic CRPC, same main points.7

Again, we’re looking like we kind of were sharing notes— a 74-year-old [median age], similar PSA doubling times. Everything is really, really similar across the trials.

Now, looking at that HR [for MFS, it was] 0.41 [40.4 months with darolutamide vs 18.4 months with placebo]. But remember, we can’t really compare it directly [with the other trials]. And if you looked at it as a number, we’re looking at almost 2 years of difference in MFS. The OS [was also] very similar [HR, 0.69].8

SOLANKI: The numbers are quite different. You talk about almost a 4:4 difference in the number of patients in the darolutamide arm vs the apalutamide arms.

EFSTATHIOU: [Looking at] the darolutamide [data in ARAMIS], you have 955 [patients in the darolutamide arm] and 554 [in the placebo arm]. In SPARTAN, 806 [patients were in the apalutamide arm] and 401 [were in the placebo arm]. Then, in the PROSPER trial, it was 933 [patients in the enzalutamide arm] and 468 [in the placebo arm]. So, it’s more of a statistical thing. It was 2:1—not a big difference.

SOLANKI: Mainly the lower numbers tend to produce a smaller HR.

EFSTATHIOU: Absolutely

SOLANKI: And so, I’m not sure that this was putting that much emphasis on the HR to compare the studies.

I [think] darolutamide [has] better tolerance [compared with the other 2 agents]. If one looks at the stratification of these patients, [the ARAMIS trial] had a much better mix of patients, more like what you call a real-world mix of patients. I had looked at all these 3, and if we just look at the HR, it looks like this one is better than [others].

EFSTATHIOU: We had a lot more of the SPARTAN [patient population] in North America than what was [seen in] ARAMIS, which was largely done in Europe and the rest of the world. They always keep [about] 10% in all the trials from Asia-Pacific because it’s a special population. In fact, they block us from accruing when they’re keeping those slots for [these patients]. So, you’re 100% right, but we have to say that the other trials represent a lot more of the North American population [than ARAMIS does]. So, that’s the difference, and it’s a very different population in how much they’ve been treated in the first line. But you’re 100% right.

CHALLAGALLA: Didn’t the SPARTAN and ARAMIS trials include patients who are node positive, as opposed to the PROSPER trial? There was N1 disease, I think.

EFSTATHIOU: It was 22%, approximately. The presence of lymph nodes in ARAMIS was 17%, with a little bit more on the placebo [arm]. You’re right: They have a little bit more, but you would not consider it imbalanced based on their statistical [analysis].

CHALLAGALLA: But PROSPER didn’t have any N1 patients?

EFSTATHIOU: Yes, they did—but I don’t think they reported as they should. It was another problem in their design. I know that they did, because I had patients who were node positive in my accrual. So, it was a little bit of a different [subset of] disease. Keep in mind that enzalutamide was coming in as the approved drug, so they did not have as much at stake as both the others had. That’s why you see more detailed databases coming out of the other 2 trials.

Targeted Oncology: What was the safety profile like for darolutamide in the ARAMIS trial? Did any AEs of special interest emerge? How does that profile compare with those of the other trials?

EFSTATHIOU: There is really no difference [between the 2 arms in ARAMIS] in falls, unlike what was the case for apalutamide. So, this has not been fully interpreted, and again, we should not compare across trials like this. But it raises the question: What is the impact, the reason, the rationale for these falls?

If you ask Mathew Smith, MD, PhD, he will say that it has to do with the brain barrier. My experience with apalutamide from SPARTAN is that I did not get dizziness. My patients were getting more muscle loss. And the question is: Don’t you have that with darolutamide?

CHALLAGALLA: I think you’ll [see] loss of muscle mass pretty much [with] all these drugs [with] ADT. I think the blood-brain barrier penetration is less so with darolutamide, probably; that’s why it seems as [if it’s] because of lesser AEs.

EFSTATHIOU: There is no [blood-brain barrier penetration] with darolutamide.

CHALLAGALLA: OK, so fewer central nervous system AEs, maybe.

EFSTATHIOU: Correct, but this is the interesting part: You have 15% of patients with apalutamide having a weight decrease, and I noticed it was not [due to] a loss of appetite. They were losing weight [for some other reason]. This is our own experience; we measure. [In other settings, it’s often] not done in a way that’s regimented. Well, we went back and looked at the change in their fat, and it was not fat loss. The only thing we can assume, then, is that they were having more muscle loss. This is something that needs to be prospectively validated and tested more, because that will change how we treat these men with regard to actually intervening and asking them to do more physical exercise. This will become very important, I think, in the future.

Returning to the AEs of interest that we discussed earlier…the main point for apalutamide is the newcomer, the rash. The mental impairment is not really a problem. It looks across the 2 trials; it becomes a little bit more with enzalutamide, as expected. But the falls—there’s a big difference in falls when it comes to the 3 trials. And again, one will say, SPARTAN was done with assessment every month and the other one was every 4 months. You can’t really do direct comparisons, but there’s an obvious signal.

Targeted Oncology: How do you decide which of these 3 agents to use?

EFSTATHIOU: We [have] here 3 trials that have similar patients, ranging from 1200 to 1500 patients, in which the key inclusion criteria are also very similar....The differences, for all purposes of looking across trials, are not there in efficacy. If anything, what we’d have to say is that the safety profile with darolutamide has less of an impact. So, as time has gone by, I have to be really honest in telling you that I’ve been using darolutamide more and more for [this population].


1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2021. Accessed March 30, 2021.

2. Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546

3. Small EJ, Saad F, Chowdhury S, et al. Apalutamide and overall survival in nonmetastatic castration-resistant prostate cancer. Ann Oncol. 2019;30(11):1813-1820. doi:10.1093/annonc/mdz397

4. 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

5. Erleada (apalutamide). Prescribing information. Janssen; 2018. Accessed May 7, 2021.

6. Sternberg CN, Fizazi K, Saad F, et al; PROSPER Investigators. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892

7. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671

8. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342