Highlighting Oxybutynin Impact on ADT-Induced Hot Flashes in Prostate Cancer

Hot flashes remain a prevalent and distressing sequela of androgen deprivation therapy (ADT) for patients with prostate cancer, often significantly impacting quality of life. CancerNetwork® spoke with Bradley J. Stish, MD, section head of Radiation Oncology and radiation oncologist specializing in genitourinary cancers at Mayo Clinic, about the phase 2 Alliance A222001 trial (NCT04600336) regarding the use of oxybutynin (Ditropan) as a non-hormonal intervention for managing these symptoms. Data suggest a dose-dependent benefit, with 5 mg twice daily offering the most robust symptom reduction, though a 2.5 mg twice-daily dose remains a viable starting point for patients with baseline anticholinergic concerns.

Stish further highlighted the rapid onset of relief, comparable to agents such as venlafaxine (Effexor) or gabapentin (Neurontin), with improvements often noted within the first 1 to 2 weeks. While xerostomia is a common adverse effect, management strategies such as hydration, sugar-free gum, and humidification can support treatment adherence. Although oxybutynin has a long-established safety profile in urology, Stish noted that future phase 3 research should prioritize evaluating its long-term neurocognitive impact in older patient populations.

Ultimately, Stish suggested these findings may provide clinicians with an accessible, flexible tool to mitigate the broad interference that hot flashes exert on sleep, work, and social activities, reinforcing the importance of proactive symptom management across both specialty and primary care settings.

CancerNetwork: Given a clear dose-dependent benefit with oxybutynin at the 5-mg twice-daily dose, would you recommend starting all patients at the 5-mg dose, or is there a specific patient profile where the 2.5 mg dose might be clinically preferable?

Stish: When we’re thinking about which dose to use clinically in patients, the study provided us with good data that are open to flexibility for both patients and physicians or providers. If you’re trying to get the biggest bang for your buck in terms of reduction of hot flash symptoms, I think 5 mg twice daily was the clear winner in our study. But we still saw a meaningful improvement in many symptoms with the 2.5 mg, twice-daily dose.

Many times, this becomes a discussion between the physician and the patient regarding their goals of treatment, and whether there are any specific factors in their case that may make you inclined to consider a lower dose. We know some of the [adverse] effects of the drug can be pretty predictable—things like dry mouth or constipation—and if there’s a patient who may have baseline symptoms in both of those domains, it may be wiser to start at a lower dose and see if you can get an effect that’s desirable, knowing you can always increase that dose if the effect isn’t quite what was hoped originally. Similarly, if we have patients who start at the 5-mg twice-daily dose, and we’re seeing [adverse] effects that are bothersome or prohibitive, physicians can feel comfortable decreasing that dose in half. Having that flexibility is nice for both patients and physicians to ensure that they can find the right dose for their specific situation.

What strategies do you employ to manage dry mouth while maintaining the 6-week treatment adherence seen in the study?

Our protocol didn’t necessarily specify any measures, so this really becomes about clinician experience and strategies they’ve learned over time, and sometimes [patients] come up with their own strategies. When it comes to dry mouth, frequent hydration is a good tool to manage this. That can feed into other symptoms. Knowing that patients with prostate cancer can be dealing with urinary symptoms, if [they’re] drinking lots of fluids, there can be a downstream effect there, literally. But certainly, drinking small volumes of sugar-free liquids is helpful.

We don’t want to introduce a lot of excess sugars in the mouth and cause dental problems as an [adverse] effect. Sugar-free gum is another good strategy to help manage that. Sucking on hard, sugar-free candies is another way to promote those salivary glands in the mouth to stimulate more secretion of saliva. Then, humidification, especially in some of our colder climates in the winter months; if you have indoor heating running, that can dry out the air in the house. The idea of keeping a humidifier where you’re sleeping [because sleep] is a common time when people notice dry mouth more regularly. Those are strategies that I’ve seen employed that have been effective at managing [dry mouth].

Then, as we mentioned previously, thinking about the dose that you’re using and whether there can be a modification of the dose that might be reasonable to achieve the same effect while decreasing the [adverse] effect profile of the drug.

How does ‘speed-to-relief’ within the first week compare with other non-hormonal options like venlafaxine or gabapentin?

We were heartened to see [a] rapid onset of symptom improvement with oxybutynin. This compares similarly with other drugs that have been studied in this regard. In most of the studies looking at hot flash remedies for men on hormone therapy, we’ve seen a quick reduction in symptoms within the first 1 to 2 weeks, whether that’s gabapentin, venlafaxine, or megestrol, amongst others, that have been looked at in this realm. It’s nice to know that we generally have a few different options that all have this rapid onset of symptom relief. You do not have to wait a long time to see the benefits of taking this drug.

Which specific domains of interference, such as sleep, work, or social activities, show the most significant improvement with oxybutynin?

It’s hard to compare across domains in terms of which is the most significant. You can get a numerically significant improvement in one domain, but it’s maybe a small part of your life. If, for example, work is one of those domains, but you’re a retired person, that may not be as important to you as sleep or other things. The takeaway was that we saw broad and deep improvement across many domains with the oxybutynin.

It wasn’t restricted to 1 specific access or symptom that was caused by the hot flashes. We have patients who come in and say, “The worst thing about the hot flashes is how they interfere with my sleep”, or “The worst part about my hot flashes is I can’t be as physically active. I’m not able to golf or go fishing as much as I was before.” We can look at this study and say this drug wasn’t restricted to 1 small part of quality-of-life improvement in these patients, and we can tell them that there’s a good chance that they will benefit with the symptom or the domain that is being bothered and affected the most for them.

What do we know about the long-term safety and durability of oxybutynin for chronic hot flash management?

This study was specifically looking at a 6-week study protocol. We don’t have follow-up beyond that 6-week time frame for these patients, but because oxybutynin is a drug that’s been around for many years and has been used in thousands of patients to manage bladder symptoms as the most common use, we have experience with patients being on this drug for long periods of time. The clinical experience has shown that, generally, the [adverse] effect profile is fairly predictable.

It’s tolerable for most patients, and we don’t see significant increases in safety concerns over extended periods of time. While our study wasn’t specifically designed to assess long term safety and effectiveness, there’s no reason to think that it shouldn’t be reasonable to use this drug for periods of time longer than 6 weeks, as long as the patient is closely monitoring their symptoms and following up regularly with their clinicians to report any concerns and be monitored for any unexpected long term [adverse] effects.

Do you believe that oxybutynin should be considered a first-line non-hormonal standard-of-care for ADT-induced hot flashes, and has this already changed the prescribing patterns at institutions such as the Mayo Clinic?

Our study was really important in demonstrating that oxybutynin is an excellent option for patients who are having hot flashes related to hormone therapy. It was meant to add to the existing literature and the options that are available. Our goal was to provide clinicians and patients with yet another option to manage their symptoms if [they] were affecting their quality of life or negatively impacting the way they went through their day-to-day functions.

Any of us can aspire to future studies trying to compare some of these active agents directly, head-to-head. It’s challenging to compare across studies that were done slightly differently in different eras with different groups of patients. We try not to draw direct comparisons between the studies that were done previously in agents other than oxybutynin, but in a broad strokes picture, we can say we saw similar trends across all these studies.

All of these are good drugs and good options, and we’d rather let clinicians and patients decide for themselves which one works best for them, understanding that there are some pros and cons of all of these agents, and that if one doesn’t work, you can then pivot to a different option that may be more effective for you.

What would be the key priorities for a phase three confirmatory study?

We’ve talked about where we go from here in terms of learning more about oxybutynin and then hot flash management in patients with prostate cancer. A few things that are clear about our study are that having a larger patient cohort is always beneficial. [Can] these results be replicated in a broader group of patients? The more patients you accumulate, the more specific niches or nuances of the prostate cancer domain, or men with hot flash domain, that you get. You get a broader age range of patients, patients from different socioeconomic backgrounds, different geographies, [or] different states of their disease. Then [you] can start asking nuanced questions about whether oxybutynin works differently in some of these subgroups of patients than it does in others.

The other thing that we would look at is, can we extend this out to see if there is a longer benefit or any concerns about using this in a longer timeframe? One of the questions that is appropriately raised, and is unanswered, about oxybutynin is, does this have an impact on memory or neurocognition? This is one of those things that gets mentioned a lot in the literature. There is some pharmacologic rationale behind how oxybutynin can have effects on memory, especially in older patients, recognizing that many patients with prostate cancer are older rather than younger. High-quality studies assessing how this impacts neurocognition through standardized testing and rigorous reporting haven’t been done, and that’s something that would be of interest to study if we were to move forward to phase 3 studies.

Is there anything else that you would like to highlight that we have not already discussed?

[I want to] highlight this symptom that is maybe underrecognized in some aspects of clinical medicine. Those of us who treat patients with prostate cancer on a routine basis, obviously, are quite aware of this. But we may have clinicians who are primary care providers who have a small number of patients that have prostate cancer, and bringing this awareness to them that a drug they are probably comfortable in prescribing in oxybutynin is something that could be used to manage hot flash symptoms, and they wouldn’t necessarily need to rely on a specialist like a urologist or a medical oncologist or a radiation oncologist to help handle that symptom.

Also, encouraging patients that if they are dealing with hot flash symptoms, it’s not just something they have to deal with. There are options to help them manage. They should feel comfortable talking to their clinicians and their care teams about some of these strategies and whether it’s right for them to help decrease those symptoms if they’re negatively impacting their quality of life.

Reference

Stish BJ, Mazza GL, Nauseef JT, et al. Alliance A222001: oxybutynin versus placebo for the treatment of hot flashes in patients receiving androgen-deprivation therapy for prostate cancer. J Clin Oncol. Published January 26, 2026. doi:10.1200/JCO-25-01486