Updated safety data and treatment selection in nmCRPC

Audrey Sternberg: Can you discuss the updated safety data for darolutamide and apalutamide that was presented earlier this year at ASCO [2021 American Society of Clinical Oncology annual meeting] and ESMO [European Society for Medical Oncology Congress 2021]?

Aaron Berger, MD: Yes. This is a longer-term assessment of the side effect profile of these drugs that was presented earlier this year. This essentially reinforced the fact that the side effect profiles are very similar even with longer treatment. As I mentioned earlier, darolutamide did not have a significant increase in common side effects compared to placebo. And with apalutamide, they’ve done quality of life surveys as well as adverse event surveys. The quality of life was not significantly impaired compared to placebo for the patients in the apalutamide arm. The updated data reinforce the fact that these are very safe, effective and have a very low incidence of adverse events that are important to everyone.

Audrey Sternberg: Can you discuss the data on the timing of adverse events with these agents, particularly in relation to the ARAMIS trial?

Aaron Berger, MD: As for timing, in my experience most fatigue or any other significant issue with darolutamide usually happens relatively early. This is true for everyone when it comes to adverse events such as fatigue and dizziness. But with prolonged exposure to these drugs in the analysis of follow-up data, no significant adverse events suddenly started to occur with longer-term follow-up. It was pretty consistent with the first data.

Audrey Sternberg: You mentioned this earlier, but would you like to mention something else about the treatment of adverse events when your patients manifest them during treatment?

Aaron Berger, MD: With any new drug, you want to make sure patients understand. We are working to obtain patient education materials for all 3 drugs. The companies behind them provide very good information materials for patients to go over the appropriate dosage and potential side effects. And then, it’s up to us, as prescribing physicians, to understand their other medical conditions, the other medications they’re taking, and to work with our pharmacy staff or the dispensing pharmacist to make sure it there are no significant interactions. These things get very complicated with all the drug interactions. There are so many new drugs coming out for all kinds of other medical conditions, whether it’s hypertension, diabetes, or other cardiovascular issues, that it’s very difficult to keep track of all the drug interactions. We rely on our pharmacy software as well as the pharmacist to help us with this. It’s really important to educate them.

When it comes to overall management, certainly give them expectations about what can potentially happen. I don’t think we want to try to hide the potential negative effects. We want to be upfront with patients about what might happen. But the overall message is that the incidence of significant high-grade adverse events with any of these drugs is quite low compared to placebo in all trials, and they are very effective. It improves their overall survival and their survival without metastasis. And for those patients who have progressive cancer, it’s number 1 on the top of their minds. They are not necessarily worried at the start: “Am I going to be a little tired? Could I have a rash in 3 months? This is not their main objective. Their goal is to better control their cancer and get their PSA [prostate-specific antigen] down. These patients are very focused on that number, as we do as well. We want to try to reduce the numbers for them, which certainly gives them a good reinforcement.

But if they have any significant new symptoms, whatever they are, they are encouraged to call me, my pivot nurse, the pharmacy, and then ask, “Could this be from the drug?” And if we think it does, we’ll potentially give them a break and then see if it goes away.

Audrey Sternberg: How does the safety profile of a treatment influence your choice of therapy?

Aaron Berger, MD: We certainly don’t want to give patients something that we know has a high risk of side effects. The good thing about these 3 drugs is that the risk of significant adverse events is quite low. With patients who have significant cardiovascular disease, such as a recent MI [myocardial infarction], recent congestive heart failure, treatments, things of that nature, we want to be careful. Some data from the trials indicate that there may be an increased risk of cardiovascular events with these drugs, especially in high-risk patients. For patients who have very high risk heart disease, cardiovascular disease, you may want to delay the start of treatment or discuss it with their cardiologist. Although sometimes the cardiologist is not as familiar with these drugs, just as we do not know much about cardiovascular drugs.

This is an area where we need to move forward: getting more resources available in terms of expertise to help us determine what is safe for these patients with cardiovascular or neurological diseases, so that we can better guide our patients. Because we certainly don’t want to hurt. This is obviously one of the major pillars of medicine: do no harm. We don’t mean to harm, but the data on all of these drugs is very clear in terms of the benefits. The data also shows that the adverse event profile for all 3 of them is quite favorable overall, so it is definitely worth a try for patients, unless they have an obvious contraindication.

In terms of who needs to be treated in general, if we’re not sure whether a patient really needs treatment, the other thing that we do a lot more often now is genetic testing for patients who do. meet the conditions. If they have a genetic mutation that may portend higher risk cancer, these are patients for whom you may want to start treatment earlier rather than waiting for their PSA to progress further and their doubling time. becomes faster. These patients may have a more aggressive course depending on their genetic profile.

This transcript has been edited for clarity.

Martin E. Berry