Efstathiou Compares the Efficacy and Safety of AR Inhibitors in Nonmetastatic CRPC


During a virtual Case Base Peer Perspectives event, Eleni Efstathiou, MD, PhD, a discussed treatment options for a 57-year-old African American man with nonmetastaic castration resistant prostate cancer.

Eleni Efstathiou, MD, PhD

During a virtual Case Base Peer Perspectives event, Eleni Efstathiou, MD, PhD, associate professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX discussed treatment options for a 57-year-old African American man with nonmetastaic castration resistant prostate cancer (CRPC)


October 2016

  • A 57-year-old African-American man is referred to urology with prostate-specific antigen (PSA) of 6.8 ng/mL
  • Medical history: seizures, controlled with medication (oxcarbazepine)
  • Family history: breast cancer (mother, sister), pancreas cancer (brother)
  • Digital rectal exam: no nodules or induration
  • Prostate mpMRI (3T):
    • Volume: 58 cc
    • Index lesion to left peripheral zone: PI-RADS 4/5, 1.8 cm
    • Seminal vesicle infiltration to left seminal vesicle

November 2016

  • Mechanical fusion biopsy:
    • Systematic: 4/12 cores positive, Gleason Group 3 (3+4), 75% involvement
    • Index lesion biopsy: 3/3 cores positive, Gleason Group 4 (4+4), 70% involvement
  • Bone scan/CT scan: negative for metastases
  • ECOG performance status: 0

February 2017

  • Robotically assisted radical prostatectomy and extended lymph node dissection
  • Final pathology: pT3bN0R1M0, Gleason Group 4 (4+4), positive surgical margin to apex
  • 6 weeks postop: PSA 0.15 ng/mL; baseline serum testosterone 420 ng/mL
  • Recommendation by urologist: adjuvant radiotherapy to prostate bed due to positive margin, pT3 disease; patient refused.
  • Patient refused salvage radiotherapy.
  • Restaging (bone/CT scan): negative for metastases
  • Androgen deprivation therapy (ADT) initiated, depot leuprolide 45 mg subcutaneously.
  • PSA: 0 ng/mLPSA doubling time: 8.6 months

October 2019 - Restaging

  • CT of chest, abdomen, and pelvis/bone scan: negative for metastatic disease
  • ECOG performance status: 0

Targeted OncologyTM: What are your impressions of this case?

Efstathiou: It looks [as though] after he nadired, he quickly recurred with a detectable PSA and a doubling time of 8.6 months. This is a case that’s pointing toward the nonmetastatic castration-resistant prostate cancer [CRPC] status. And in the case, we don’t have it, but testosterone would be checked, and it is within the castrate levels.

According to the case, this was followed with conventional imaging. This gentleman is now 60 years old in October 2019.

According to the case, the patient refused [radiotherapy]. Having said that, if you look at the data from the phase 3 trials that were done, you would see that 24% of patients who were included, at least in 1, had not been offered any treatment at the beginning, at their diagnosis, even of their primary [tumor]. So it’s quite impressive that still, to this day, a lot of patients do not get radiation even on the primary [tumor] when it is needed, and it calls for more education. We don’t know if these cases were from the European side, the Asia side, or the United States side. It’s not exactly granular, but it was disappointing for me to see.

Would you get advanced testing done for this patient?

I’ve been sending patients who can [go for PSMA PET] to University of California, Los Angeles, recently, because I believe that Axumin and PSMA, looking at the data, are equally sensitive. However, it appears that PSMA is more specific. I’ve had a lot of false positives on PETs. I’m not pointing fingers, but it’s from different places that I got them, so I’m not relying on the results. But, for this case, if the Axumin is still lining up in the prostate, then you have a clear move forward. But, to this day, for nonmetastatic CRPC or for PSA-recurring CRPC only, we do not have an indication to do the PET scan. That is in line with these studies being done with conventional imaging, and that can be a concern with approvals.

Now, this man was given conventional imaging, and this is more the standard across the board.

Do you actively pursue germline testing in high-risk disease or metastatic disease?

I was recently on an ad board, and I was speaking to people from Duke University, Mayo Clinic, and the like. Nobody has any systemic approach yet, and it’s not even routine in most cases. It’s up to the physicians, and it can be more taxing that way, I find, because it’s 1 more thing added and sometimes can be missed. So I hope that in the future it will become as straightforward as doing the PSA, doing the testosterone, and [other processes such as that].

What are your thoughts on the results of this poll? What would you have voted for?

Most seem to have gone for any of the novel hormonal agents. Somebody put down chemotherapy. Somebody else also voted for nilutamide, flutamide, or bicalutamide.

I would go for other.

Seventy-seven percent voted for enzalutamide [Xtandi], apalutamide [Erleada], darolutamide [Nubeqa], or abiraterone [Zytiga].

How would you compare these agents?

I’ve been starting to use [darolutamide] recently. Its approval was more recent.

I don’t see a big difference between enzalutamide and apalutamide, not only in the fatigue, per se, but also the central nervous system [CNS] effect, which has to do with some extra depression, some extra insomnia, some extra effects that are not trivial. The difference is small [between these 2]. But the claim from the preclinical data was that apalutamide would have less of a CNS impact. Of course, when you test it in humans is when you see the real deal, and more so in the real-world experience.

With enzalutamide, my experience had always been that at least I can draw a line that I can say if a patient is over 70 years old, he may not perform that well. But, more recently, I’ve even seen young men not being able to tolerate it.

And, in the case of this patient, I would say that we should all agree that both enzalutamide and apalutamide would be totally contraindicated because of the seizure disorder. So darolutamide is the only path forward.

What about abiraterone?

These [other] 3 drugs have an indication for nonmetastatic CRPC. Would you expect the insurance to go for abiraterone? I would find it hard [to believe the insurance would accept it,] because it’s not within the indication.

What are the takeaways from this poll?

Essentially, the bottom line is, you don’t see any difference in the efficacy between the 3 agents, but you see an advantage in the safety profile.

I’m starting to use darolutamide more, and I was reluctant at first. But now that most data are out, I would say I would agree; there’s nothing holding me back in that aspect.

CASE (continued)

After shared decision-making, darolutamide was initiated.

What are your thoughts on the choice of darolutamide?

[The PSA doubling time] was a major concern in the beginning and now, as of this ASCO [American Society of Clinical Oncology Annual Meeting], we have overall survival [OS] data that exceed a year in the CRPC space, which has not been shown before.

I don’t know how patients tolerate it yet. I gradually started to give it to the first patient, the second, but I’ve got about 10 patients who are on it now, so I’m getting there. It’s a big deal, because I always say that if we haven’t had the hands-on experience in research or a clinical trial, it hits the market and then you’re [deciding], “I don’t know this drug, I’m going to stay with my comfort level. I can use enzalutamide and abiraterone blindfolded, but it looks [as though] darolutamide is going to be pretty easy. I want to see their data.”

My only thing is I want to see more data coming from them with regards to bone density, and I think they’re getting ready to give those data—the effects of that antiandrogen. We’re also looking forward to getting their hormone-naїve data, which is also going to come forth. There’s a trial where investigators are combining it with chemotherapy. So it’s pretty new; it’s the new agent, but I’m feeling more and more comfortable with it.

What are the data supporting the use of the 3 newest agents—apalutamide, enzalutamide, and darolutamide—in this setting?

My impression of the NCCN [National Comprehensive Cancer Network] guidelines is that they’re there to help us get through the insurance, because most of us are familiar with the datasets. And here [with] a PSA doubling time of less than 2 months in a man who has, by conventional imaging criteria, negative disease, you can use either apalutamide, darolutamide, [or] enzalutamide—all category 1 [recommendations].1 But they’re also leaving open the option for other secondary hormonal therapy, allowing for older agents, which I think is not fair in view of all primary and secondary end points being met.

All 3 trials—SPARTAN [NCT01946204], PROSPER [NCT02003924], and ARAMIS [NCT02200614]—were identical, with a primary end point looking at metastasis-free survival [MFS] of the agent plus ADT versus placebo, and secondary end points including progression-free survival [PFS], local progression, quality of life, and OS. That was [not a] secondary end point for a lot of the physicians. They still held [off] on it until they heard the final OS data. My prior chair would say, “If I’m going to treat a patient with an agent for 3 extra years, I need to make sure I’m not compromising his quality of life or making his other morbidities worse.” But there was a point in the SPARTAN trial [of apalutamide and ADT versus ADT and placebo in patients with nonmetastatic CRPC] that was important for me. It was the only [trial] that looked at the PFS2, which essentially compared starting earlier versus starting later and showed that starting earlier is better.

I think, in the interest of science, we should not stick with, “This is what the SPARTAN trial says, this is what the PROSPER trial says, this is what ARAMIS trial says.” We have 11 phase 3 trials across the board, across the cancer with novel androgen signaling inhibitors that are all positive. There has been no negative trial, which is phenomenal. The data is superimposable. You can’t see a big difference in the efficacy. For efficacy assessment, I don’t see a difference between the agents, and I use the datasets across the board. I think they are supportive of each other rather than antagonizing each other.

The [SPARTAN] results are old news now. There was a phenomenal difference in MFS that exceeds the 2-year mark [median MFS, 40.5 months with apalutamide versus 16.2 months without; HR, 0.28; 95% CI, 0.23-0.35; P<.001].2

The new finding that was reported at the [2020] ASCO meeting [was OS], and it was a poster discussion for all 3 [trials]. I like that they made them poster discussions rather than making them big oral discussions. They left oral discussions for more innovative things, [such as] the trials that we do with finding prescriptive markers. A lot of people complained that this was a big deal and should have been more showcased, but I think the fact that they were lumped together and discussed as a success for novel androgen signaling inhibitors is enough, and now we all would agree that their use in this space is valid. The main concern is finding these patients. The OS [had] about a median difference of a little over a year, which is not trivial, for the apalutamide [73.9 versus 59.9 months with ADT/placebo; HR, 0.78; 95% CI, 0.64-0.96; P=.0161].3

I was not involved in the SPARTAN or the ARAMIS trials, but I am an investigator on the PROSPER trial [of enzalutamide and ADT versus ADT and placebo in patients with nonmetastatic CRPC], and I was [included] in this New England Journal of Medicine paper that came out where we showed an OS benefit.4 [The design of the PROSPER trial was] exactly like SPARTAN.

Similar data [were] originally presented. OS difference looking at a year again [67.0 months with enzalutamide vs 56.3 months without; HR, 0.73; 95% CI, 0.61-0.89; P<.001]. The analysis that we saw on SPARTAN is the final analysis with the longest follow-up, but this is not far behind, [with] 48 months of median follow-up.

The ARAMIS trial [of darolutamide and ADT versus ADT and placebo in patients with high-risk nonmetastatic CRPC,] was the one that took us by surprise, because a lot of us were not familiar with this agent. I was seeing it in the background when it was developed, and I could hear Karim Fizazi, MD, PhD, who’s a good friend, speaking about it. And I [said], “We already have 3, what is this extra fourth going to come through with?” And it turns out that they were right in pursuing it. Because they did exactly the same trial as the previous [trials of the other androgen signaling inhibitors], but with an agent that had all the prerequisites to be potentially safer, and they delivered.

The MFS with a short median follow-up [of 17.9 months], looking at about 2 years of difference of MFS [40.4 months with darolutamide versus 18.4 months with placebo], a hazard ratio of 0.41 [95% CI, 0.34-0.50; P<.0001]. Just as a reminder, for the other 2, it was about 0.3. Some people have commented on this, but I would not be able to compare.5

Now, their secondary end points were [more] defiant. At the first presentation, the OS was already starting to look good [with a hazard ratio of 0.71 (95% CI, 0.50-0.99; P<.045)]. It had not [yet] met their threshold, but it was close, and there was a short follow-up compared [with] the other trials.

The time to progression data [show a median time to pain progression of 40.3 months with darolutamide vs 25.4 months without (HR, 0.65; 95% CI, 0.53-0.79; P<.0001)]—the other 2 trials also had similar data, which, as I see it, are supportive of each other rather than the inverse. This, for our patients, is a big deal.

Their PFS data [showing a median PFS of 36.8 versus 14.8 months (HR, 0.38; 95% CI, 0.32-0.45; P<.0001)] confirm what I said: superimposable MFS to PFS—reinforcing the fact that the addition of a drug [such as] darolutamide, that seems to be safer, adds to these patients more time without need for further interventions and amounts to about 2 years.

The OS at a median follow-up of 29.1 months [was not reached in either arm]; it’s rather early compared [with] the rest but an obvious improvement here. The hazard ratio was around 0.69 and a P value of 0.003.6 So positive OS data for all 3 trials.

How do the safety profiles of these 3 agents compare?

[In terms of] adverse event reporting [from the PROSPER trial], the main concern, according to them, seems to be grade 3 and above hypertension and some fatigue. I would not pay a lot of attention to what is over grade 3 because when I use a drug for 2 to 3 years, for me even grade 1 and 2 matters. It makes absolute sense to use the least-compromising agent.4

Now, the [ARAMIS safety profile] the winner. They had little adverse events that are treatment related [with darolutamide] [TABLE].5 It’s impressive if you look at it versus placebo. And if you want to look at a difference that’s at least 2%, I see almost nothing. It’s impressive.

When we were working on apalutamide, I got excited because I saw for the first time that 15% of patients were getting a weight decrease. If you look at the data from SPARTAN, it shows up. If you see [the data with] darolutamide, it’s 3.6%. We started doing some measurements, and it’s [because of] loss of muscle, and it adds on to the CNS effects. So the falls are not just a result of the CNS effect; it’s also a lot of muscle weakness, as well.

Overall, how do these 3 trials and drugs compare?

Of course, we shouldn’t be [comparing these 3 trials] officially. But there is really no difference between the 3 trials when it comes to the primary and secondary end points. The only difference between the 3 trials with regard to their contact was that, in the apalutamide trial, patients came every month; in the other 2, it was every 4 months. But for MFS and OS, there’s no difference between them. They had close hazard ratios.

So we have all [these] agents approved at this point—abiraterone acetate, enzalutamide, apalutamide, and darolutamide. Abiraterone is approved for the hormone-naїve metastatic setting, and it’s also approved for metastatic CRPC; enzalutamide for hormone-naїve and nonmetastatic and metastatic CRPC; apalutamide for nonmetastatic CRPC and hormone-naїve; and darolutamide for nonmetastatic CRPC. I would argue that for me, these 4 agents have equivalence in their efficacy, and it’s more a matter of safety.

How does the use of novel imaging affect the duration of treatment and quality of life of these patients?

With the advent of enhanced androgen signaling in the hormone-naїve space, I feel that we’re adding these drugs for an indefinite amount of time. We’re going to try to do that with finite-duration hormones, so that we may get the opportunity to prolong the quality of life of the patients. But, as it’s standing right now, if you do a PET early on in the disease, you may end up treating those men indefinitely.

We know well that if you don’t take care to look out for cardiovascular morbidity, bone health, and the like, especially in the older men, you can get a tradeoff that’s not to the benefit of the patient. It’s a big discussion. But I sometimes say that 1 option is to be more diligent about making sure that the patients are followed at least by their primary care physicians and their cardiologist more carefully.

What are some of the drugs that should be avoided during use with these agents?

Thankfully most of us use electronic prescribing, so we see the drug-drug interactions show up. I don’t think we can ever remember all of that by heart.


1. NCCN Clinical Practice Guidelines in Oncology: Prostate cancer. Version 2.2020. May 21, 2020. Accessed August 17, 2020. https://bit.ly/32pmz7H

2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide (APA) and overall survival (OS) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): updated results from the phase III SPARTAN study. Ann Oncol. 2019;30(suppl 5):v325. doi:10.1093/annonc/mdz248

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;30(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516

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

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

6. Fizazi K, Shore ND, Tammela T, et al. Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;38(suppl 15):5514. doi:10.1200/JCO.2020.38.15_suppl.5514

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