Hormonal Therapies Useful in Different Situations for Prostate Cancer

Daniel James George, MD

During a Targeted Oncology Case Based Peer Perspectives event, Daniel J. George, MD, professor of Medicine, professor in Surgery Member, Duke Cancer Institute Department of Medicine Duke University School of Medicine, discuss various hormonal therapies for the treatment of prostate cancer.

Targeted Oncology^TM: Is there a role for hereditary germline testing in this patient?

GEORGE: He has not exhausted all of the treatment options. He has not even really been treated yet for his castration-resistant prostate cancer. He’s nonmetastatic by our standard imaging, and yet he’s relatively young for the disease, and [he has] a relatively rapid natural history, localized disease to castration-resistant [disease] in a couple of years. And don’t forget, he has a family history of breast cancer and pancreatic cancer in his mother, his sister, and his brother.

[Also,] you don’t know where the other family members stand in terms of these possible diseases….There’s a sister and [she has] 2 brothers, 1 with pancreatic [cancer] and 1 with an aggressive prostate cancer. This is going to be a lethal prostate cancer, maybe not now, maybe 5 years from now, but it’s going to be a lethal prostate cancer. [I suggest] getting that family history out there and then doing the testing, because if it’s a BRCA2 prostate cancer…that’s important for them to know. And if it isn’t [BRCA2 prostate cancer], are there other germline alterations? I think it’s important to do it. When I do it, I’ll send a broader [panel], not just the BRCA2. I’ll send it for 40 different germ-line alterations. It’s not that much more money to do that, and I think it solidifies the whole picture. It’s another reason to do it sooner rather than later.

What are your thoughts on the results of this poll?

[Everyone chose] novel hormonal therapy; there it is, a rare consensus. It’s exactly right…for a lot of reasons that makes of sense. He’s young [and he’s] had this rapid natural history. Even though a PSA doubling time of 8 months isn’t terrible, it’s not the best, either. For people with doubling times of [more than] a year, I’d take a different approach. But for doubling times under a year, particularly under 10 months, these are exactly the patients we tested with these novel hormonal therapies and [who] demonstrated clinical benefit.

Which hormonal therapy would you strongly consider?

We’re talking about the novel hormonal agents, and there are 4 of them in that list: enzalutamide [Xtandi], apalutamide [Erleada], darolutamide [Nubeqa], and abiraterone [Zytiga].

How do you choose among these agents?

Sometimes we think, “Darolutamide, that’s for older people because it’s not as toxic.” But for a 57-year-old [patient]…I would [assume that] he’s still working, he’s probably still working out, he’s still active. And a drug [such as darolutamide] is still going to make him tired at the end of the day, especially if he’s pushing himself….[Being] on a drug where you can still maintain that active lifestyle, that active work life, is important. I don’t think of this as a drug necessarily just for older people, although I think older people tolerate it well. I think of it as a drug that is probably the most compatible with maintaining an active lifestyle.

These drugs were approved on an end point of metastasis- free survival [MFS], and that’s a novel thing in the field, but clinically, I don’t know what to make of that. I know it’s a progression, but is it a clinically significant progression [if it just goes] from a disease that’s below the threshold of detection to above the threshold of detection? But when I saw that translate into overall survival [OS] benefit in the last year, and not a subtle survival benefit but a meaningful survival benefit, that pushed me into treating more patients in this nonmetastatic castrate-resistant space….This isn’t a lead-time bias where we’re just giving the drug earlier than giving it later; these are patients in the control arms who are still getting these treatments. And yet, early treatment in the nonmetastatic low-volume setting is improving survival, and that says that timing matters in this disease. Especially with younger patients, but really any patient, even my 80-year-old patients who I think are going to live for 5 years or more, I’m going to be encouraged to treat them earlier rather than later based on that survival difference. So that to me was a meaningful end point.

[It’s not just] darolutamide. We’ve seen this across the field—apalutamide and enzalutamide also showed survival differences. To me the data look comparable between all the agents, so I can’t pick a drug based on efficacy. It gets back to quality of life and experience with these drugs. Even though darolutamide is a twice-a-day pill, that hasn’t been a problem for our patients.

Is there a space for these novel hormonal therapies even earlier?I think we’re going to have some studies that…answer this question. Every time we’ve moved these drugs up earlier in the natural history of the disease, we’ve seen clinical benefit. What I don’t know is at what point we are introducing lead-time bias. At some point you’re going to get longer and longer exposures to these drugs and you’re going to have more cumulative toxicity. So [some] of the concerns, even with a drug [such as] darolutamide, [will be] losing muscle mass, losing strength, increase metabolic syndrome risks, and cumulate more frailty in some patients.

Now, I’m less worried about it in an active 57-year-old patient, but I’m more concerned about this in some of our older patients. So, to the extent that we could, I think this is somebody we might have considered that in, but it would be off label. I think right now it’s not as compelling to me, it’s not as critical until I see this early castration resistance. That’s my trigger to say [we have] to get those drugs on board.

Do you use novel imaging methods, and would they change your treatment strategy here?

Yes, we do. We have an investigational new drug for PSMA [prostate-specific membrane antigen], very specific, so we can’t [use it in] all-comers, but we have access. We have a couple of trials, [including the]…SPOTLIGHT study [NCT04186845] looking at a PSMA. [We have Gallium 68 PSMA-11], but I would say for most of our patients we still use Axumin [fluciclovine]. Axumin has been a good measure for us, and we’ve used that one. It doesn’t change my use in this space, though, because I think a lot of the patients who are included in these nonmetastatic resistant trials were patients who probably had Axuminpositive disease, and we didn’t get a chance to confirm it, but it’s the same biology.

[Novel imaging] would give us a better insight into what we’re dealing with and maybe a bit more transparency on the disease state. But it’s probably not a different biology, so I’d still think of using these agents even in patients with positive metastatic disease by novel imaging only. As long as that CT scan is still negative [and the] bone scan is still negative, I think you’re on good ground for using these agents.

What if the patient is positive on PET scan?

It’s a good question, because what if an insurance company says [it is] not going to pay for darolutamide because [the patient has] a positive PET scan? They say, well, it’s metastatic and you can only use enzalutamide. Apalutamide is not approved for metastatic disease. Darolutamide is not approved for metastatic disease. We can run into a bit of trouble, so be careful what you wish for. Sometimes I don’t do that novel imaging specifically because I don’t need to know that. If the CT scan and bone scan are negative, that’s enough for me. I tend to save it for circumstances where I think…there’s something else going on.

Could radiation be beneficial in this setting?

We have a clinical trial we’ve written now doing just that with these agents in the early castration-resistant setting to see if we can get that complete response approach [with radiation] and [by] adding immunotherapy, believe it or not. We’re looking at strategies to do that. We look at radiation, not as [perhaps] the cure in these patients, but [asking if it could] elicit more antigens, neoantigens, and other immune response to make these tumors more recognizable to the immune system.…I would say that, in my experience, most of the time when I treat oligometastatic disease, these patients still continue to progress. But maybe 20% to 30% of the time we’ll get a prolonged disease control with that. So, it’s not unreasonable. I’m not sure there’s ever going to be an FDA indication for that approach, but it’s the kind of thing where the more confident I am that it’s oligometastatic, the more I’ll consider those kinds of approaches.

What do you take away from the responses to this poll?

We’re seeing, as you’d expect, a nice spread of treatment options for patients. I think a lot of this is based on experience of what people have used, and I think that’s important for people to base it on that. How we get comfortable with drugs is [by] using them, and this is a setting where I think you could use any of those 3 selected. I’m glad nobody [chose] abiraterone. I think that’s not really the indication for abiraterone, and [it would mean] a lot of prednisone exposure if you [used it]. I agree with all of those choices. I think they’re all really good ones, but they are slightly different.

What other factors would have influenced the treatment selection that would lead to the choice of darolutamide?

This patient’s history of seizures…might affect your choice. I think seizures are something that both apalutamide and darolutamide excluded in their studies, and so we don’t have a lot of data. We did a study of enzalutamide in patients with a prior history of seizure, brain trauma, and other seizure risks, then published those results.1 The reality is it’s not high, but we did see a seizure incidence associated with it.

The interesting thing about darolutamide [is that] it doesn’t cross the blood-brain barrier, so it has no contraindications for patients with seizures. If you have patients with seizures, even if they haven’t been active in years, it’s something patients are very aware of. Once you have a seizure, that’s it for driving for 6 months. That potentially affects your work and other aspects, so it’s a significant quality-of-life effect, and it’s something I think patients with that history are trying to avoid.

What if the PSA doubling time were 15 months? I mentioned this earlier. At what point [does] PSA doubling time become so slow that the natural history doesn’t justify it? For me, 15 months is too slow. When I see that, I tend to sit back and say, “OK, we can watch this disease for some period of time,” but I’m following it still. [I’m doing] PSA checks probably every 6 months or 3 months to make sure that PSA doubling time doesn’t change.

In your experience, how does darolutamide differ from the other agents in its class? I see less dizziness, less unsteadiness. It’s probably a little bit more pronounced in my older patients, [who] are more prone to falls or imbalances, and some of that may be comorbidities, if they have neuropathies or other things. It’s anecdotal but the drug may be better tolerated.

So far with darolutamide, in my experience, even with the majority of my patients who are older, they’ve been able to tolerate it with some fatigue, but not disproportionate, and none of the central nervous system stuff that some of the other drugs have been associated with. I haven’t seen the level of rash that, say, we’ve seen with apalutamide.

What were the data that supported each of these agents in the class?

The apalutamide study [SPARTAN (NCT01946204)] was a 1200 patient study randomized 2:1 to apalutamide or placebo, again [with an] MFS primary end point but secondary end point [of] OS.²

[For] the primary end point of MFS, [there was] a huge treatment effect. It’s what led to the approval by the FDA because it wasn’t just positive, it was way positive, really a doubling of that MFS [40.5 vs 16.2 months; HR, 0.28; 95% CI, 0.23-0.35; P < .0001]. And it translated into OS, [which is] the important thing [73.9 vs 59.9 months].³ You didn’t see that in the first 2 years, but after 2 years, these curves started separating and they stay separate. The hazard ratio was 0.78 [95% CI, 0.64-0.96; P = .0161]. You could say, “Wow, that’s not a huge hazard ratio of 22% improvement in survival.” But these patients are living out their 6 years, so 20% of 6 years, that’s [more than] a year of survival benefit. That’s more than what we see in the metastatic castration-resistant setting with these drugs. So, it may look subtle, but it’s a pretty dramatic improvement in survival. [It is] a 14-month improvement in median survival.

Some of the [adverse] effects we talked about—[some of them are] a class effect. You’re going to see fatigue, hypertension, diarrhea, falls. You say, “Oh, falls, that’s not really drug related,” [but falls are] drug related. We see twice as many falls in the apalutamide group as in the placebo group. Some of the other things are a bit less concerning. Still, these are long-term, significant effects.

PROSPER [NCT02003924] was the enzalutamide study. Again, [it was a] big study of 1400 patients with 2:1 randomization. This is again MFS and then OS [for end points].⁴ [The patients had the] characteristics of median age in the 70s and median PSA doubling time of 3.6 to 3.8 months. These are [patients with] fast PSA doubling times.

[There was a] dramatic difference [in MFS], 14.7 months versus 36.6 months [HR, 0.29; 95% CI, 0.24-0.35; P < .0001], with an almost 2-year difference in MFS. Then those OS curves were beginning to separate there at maybe 24 months. They continue to separate out and, again, [there was a] hazard ratio of 0.73 in this case, 67.0 versus 56.3 [months], and about a year’s improvement in OS [P = .001].

The toxicities [of] hypertension [were] significant [5% vs 2%], doubling in the hypertensive rate, and fatigue [3% vs 1%] [was at] grade 3 levels. The grade 1/2 rates were much higher, but the grade 3 rates are the ones that are going to change our management of these patients. [Those] are important to keep track of, [as well as] coronary artery disease and acute myocardial infarction. There are some cardiac risks with this, and again we’re dealing with an older population, but nonetheless, this is something that we balance with these drugs.

The third one [is] the study ARAMIS [NCT02200614] of darolutamide in 1500 patients.5 This is our largest trial; [patients received] darolutamide twice a day plus ADT versus placebo, with a 2:1 randomization. Again, you see that median age around 74 [years old], ranges again from 50 to 90, median PSA doubling time of around 4.5 months—a relatively fast PSA doubling for this population.

We see [once more] this dramatic difference in the MFS, about a 22-month improvement in MFS [40.4 vs 18.4 months]. Then [we see] this OS, and this is the newest trial so it’s the least mature. But, again, we start to see around 20 to 24 months.6 It’s the same pattern. These curves start to separate and that’s where you’re getting prostate cancer deaths, anywhere from 2 years out to 5 years. This is early separation resulting in a 31% reduction in the risk of death in these patients already with just 2.5 years of follow-up [HR, 0.69; 95% CI, 0.53-0.88; P = .003].

It’s interesting that we see a doubling of toxicities with a lot of these agents. With darolutamide, maybe there’s a 30% to 40% increase in the toxicity rate, and everything is relative for placebo. How they recorded it, how often they checked is important, so we do see the same patterns but maybe a lot less. And then you look at things [such as] dizziness [4.5% vs 4%], falls [4.2% vs 4.7%], not much change; fractures [were] similar.⁵ We see a bit more hypertension [6.6% vs 5.2%]. We see a bit more coronary artery disorders [3.2% vs 2.5%] and heart failure [1.9% vs 0.9%], all in that 1% range as we saw with the other agents. So I think some of that is a class effect. The things that are [related to the] central nervous system—the dizziness, the falls, imbalances, maybe the memory, concentration that was brought up, as well—are probably where this drug differentiates, not across the board but just in those very specific [adverse] effect profiles. Fatigue can be central [15.8% vs 11.4%]. Some of that can be brain mediated, some of that can be musculoskeletal. It makes sense that fatigue might be a bit less severe with this agent. But I think until we have head-to-head studies, we’re never going to know.

Overall, how would you compare these agents? Some of these patients are dying early of this disease….Early treatment with agents [such as] enzalutamide, apalutamide, or darolutamide [extends] that survival. That’s the rationale. The fact that you see these reproducible trends across all 3 studies makes it incredibly believable and important to recognize because it’s not just delaying changes in radiographs; this is extending survival.

I wouldn’t split hairs over hazard ratios of 0.7ish range for all of them and MFS hazard ratios of 0.3 or 0.4. I think they’re all significant here.

There are some drug-drug interaction differences, and I do want to point this out because I think this is another issue that maybe in the past we haven’t really thought about. Enzalutamide and apalutamide have a lot of issues in terms of drug interactions. [These are] different metabolic pathways that enzalutamide, in particular, interacts with. I know we’ve used this drug a lot. I’ve used this drug a lot, but it’s interesting that darolutamide is a different formulation [but] doesn’t have those same drug interactions. It has interactions with BCRP substrates. Those are relatively rare in our practice.

I think it’s something we’re becoming increasingly aware of as our older patients have a lot of polypharmacy going on. Just being aware of these drug-drug interactions is another rationale for choosing a different drug in class.

_References:

_{1. Slovin S, Clark W, Carles J, et al. Seizure rates in enzalutamide-treated men with metastatic castration-resistant prostate cancer and risk of seizure: the UPWARD study. JAMA Oncol. 2018;4(5):702-706. doi:10.1001/jamaoncol.2017.3361}

_{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 3 SPARTAN study. Ann Oncol. 2019;30(suppl 5):2522. 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;38(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(23):2197-2206. doi:10.1056/NEJMoa2003892}

_{5. 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}

_{6. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383:1040-1049. doi:10.1056/NEJMoa2001342}