Q&A: Jeffrey Spier, MD, on ARPI fatigue and the case for dose reduction

Androgen receptor pathway inhibitors (ARPIs) anchor treatment across the advanced prostate cancer continuum, and many patients remain on them for years. Over long treatment courses, adverse events (AEs) such as fatigue can erode quality of life, adherence, and persistence. Dose reduction has emerged as one strategy to keep patients on therapy.

A retrospective observational study of 140 patients treated with enzalutamide (Xtandi) for metastatic prostate cancer found no significant differences in 12-month progression-free survival or prostate-specific antigen (PSA) response across low-, intermediate-, and high-dose groups.¹ Fatigue worsened in 27.3% of patients in the low-dose group vs 61.1% in the high-dose group (P = .03). According to the authors, the findings warrant further study of optimal dosing.

Jeffrey Spier, MD, a urologist at Rio Grande Urology in El Paso, Texas, spoke with Urology Times® about the tolerability issues derailing long-term ARPI therapy and how fatigue affects patients’ daily lives. He outlined the clinical and patient factors guiding dose-reduction decisions and the real-world evidence on reduced-dose enzalutamide. He also discussed the trade-off between full dosing and adherence, along with the data still needed to define the strategy’s role in practice.

Urology Times: What tolerability issues most often keep patients from staying on ARPI therapy long term?

Spier: The one adverse effect that jumps out at me is fatigue. That’s the most common complaint that I get in my clinic, and I think that’s pretty universal. From there, you’ve got cognitive defects [and] CNS [central nervous system] effects. There are, of course, certain agent-specific effects like hypertension or rash, arthralgias, [and] fractures. It runs the gamut, as well as hepatotoxicity, but to bring it all home, it’s going to be fatigue.

Urology Times: How does ARPI-associated fatigue affect patients’ daily functioning and quality of life?

Spier: The first question I ask my patients is very simple: “What is the fatigue keeping you from doing?” It can be pretty severe. Most commonly, you’re looking at decreased activity [and] exercise [and worsened] mood, [and] enjoyment with life in general. It comes into more of a depression picture. How are their relations with others? Some are unprepared to manage it; they just didn’t see it coming. It speaks to the fact that counseling is incredibly important prior to placing these patients on these agents.

I feel like the real-world fatigue [rates are] much higher than [in] the trials that we’ve seen, and you’ve got to correlate that with treatment duration. In our clinics around the country, I’m sure that we see this much more than is actually in the literature.

Urology Times: Which factors matter most when deciding whether a patient may benefit from a dose reduction?

Spier: I think the most important factors include the degree of disease control. Has there been a proper and durable PSA [response]? How are they doing as far as their PSA response? I think radiographic stability is also incredibly important, but the other things you have to take into consideration are the patient factors: their age, their performance status, their risks of falls, and polypharmacy. These are all key considerations. And then [there’s] making sure that they don’t have some conditions that are already in effect, like depression, anemia, [or] hypothyroidism. These are all important factors as well. The last thing I will say is financial toxicity—we have to keep that in mind when we’re prescribing these ARPIs.

Urology Times: What does real-world evidence show about whether reduced-dose enzalutamide preserves clinical benefit?

Spier: What we’re seeing in the literature is there doesn’t seem to be a big discrepancy in PFS [progression-free survival] and OS [overall survival], but I think there’s still a lot of missing evidence out there, and we’re mostly evaluating retrospective studies. There’ll be a need to shift towards, hopefully, some prospective studies.

Broadly speaking, I think lowering the dose of enzalutamide does show that it’s preserving PSA responses and disease control, with, of course, minimizing toxicity. The tolerability seems to be linked to the initial dosing. That’s an important factor: some of the studies have shown starting at a lower dose doesn’t really make a difference. It’s decreasing the dose where the benefits become evident.

Of course, you’ve got to also understand that these drugs are sometimes being given to more frail patients, the elderly, and so there may be some bias there. So again, I think we need some further studies, especially prospective [studies].

Urology Times: How do you weigh full-dose benefits against the risk of poor adherence or discontinuation?

Spier: We’ve seen in different settings, including EMBARK (NCT02319837) and STAMPEDE (NCT00268476), that discontinuing for adverse events is not trivial. It’s been shown that [patients] just don’t want to take it, and they stop it. It’s better to stay on it, of course, than to discontinue the medication. That’s where this dose adjustment discussion is paramount.

You have to set expectations for fatigue and other common [adverse] effects. That’s where the educational support comes in, mentioning to the patients that these AEs are modifiable. We have to have that discussion that there are workarounds, but it is definitely ominous to look at some of the data on discontinuation rates. Some is better than none would be my philosophy.

Urology Times: Does the approach to dose reduction differ across ARPIs (abiraterone [Zytiga], apalutamide [Erleada], darolutamide [Nubeqa], and enzalutamide)?

Spier: It absolutely does. The mechanism of action is different, and so the toxicity profile is going to be different. There’s a different approach, and it’s agent specific. Without getting into too much detail, with enzalutamide, you’re looking at fatigue, cognitive [effects, and] CNS effects. With abiraterone, we’ve got hepatotoxicity that we have to deal with, [as well as] hypertension [and] hypokalemia, all of these things that we have to be very careful about. With apalutamide, we commonly see rash, and darolutamide, of course, also has some fatigue factors.

It’s definitely a different approach, and dose reduction has to be at least discussed. But I think it’s universally accepted that it’s something that is an option for the full spectrum of ARPIs.

Urology Times: What should clinicians monitor after reducing an ARPI dose?

Spier: One of the nice things about having these advanced prostate cancer clinics that are sprouting up all over the country, especially in the independent urology space, is the consistency of care and follow-up. I think having a cadence to follow-up [matters]. Certainly within the first month, we like to have our patients come in for a PSA. We also want to confirm that they’re castrate [by checking] testosterone, and then [get] imaging if necessary in time. And then we have a 3-month follow-up with consistent PSA readings, as well as other laboratories, including LFTs [liver function tests], etc.

I think there’s a need for constant rescreening when we’re visiting with them, using different validated tools to see how they’re doing on the reduced dose, and [to] reescalate if we can. That’s the goal. If they’re able to tolerate the full dose, then I think the discussion of reescalation is important as well.

Urology Times: What additional evidence is needed to clarify the role of ARPI dose reduction in routine practice?

Spier: I want to stress [that] randomized prospective studies are going to be important. I also think that we need to do a better job of demonstrating patient benefit and measure it a little bit more properly. The other thing about these studies is we have to be careful with selection criteria, because again, a lot of our patients are elderly and frail, and as I mentioned earlier, there can be some bias in some of these results.

Ultimately, we have to have evidence that the reduction-in-dose strategy not only improves tolerability and treatment continuity, but it’s going to have to show that it preserves cancer control. All of those things have to be measurable with future data that we’re hopeful will be more prevalent.

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REFERENCE

1. Oliva M, Boitano M, Carbone A, et al. Efficacy and toxicity of low-doses versus standard-dose enzalutamide in advanced prostate cancer: a real-world study with implications for cancer prevention/interception. BMC Cancer. 2026;26(1):115. doi:10.1186/s12885-025-15396-y