Antiandrogens Plus ADT Continue to Reign Supreme in Nonmetastatic CRPC

Michael E. Hurwitz, MD, PhD

Antiandrogen agents in combination with androgen deprivation therapy (ADT) continues to serve as the standard of care for patients with nonmetastatic castration-resistant prostate cancer (CRPC) who have a rapidly rising prostate-specific antigen (PSA) doubling time of 10 months or less, according to Michael E. Hurwitz, MD, PhD.

“Apalutamide [Erleada] and enzalutamide [Xtandi] are almost identical structurally and share similar adverse effects [AEs]. Darolutamide [Nubeqa], on the other hand, is structurally different and doesn't cross the blood–brain barrier as readily as the other agents,” Hurwitz said. “Moreover, patients seem to experience fewer AEs, such as less fatigue, falls, and fractures. As such, for patients who are worried about these AEs, darolutamide seems to be the best alternative.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Prostate Cancer, Hurwitz, MD, PhD, an associate professor of internal medicine at the Yale Cancer Center, highlighted the role of second-generation androgen blockers in nonmetastatic CRPC, how these agents compare, and active areas of investigation.

OncLive^®: The 3 key studies in nonmetastatic CRPC are SPARTAN, ARAMIS, and PROSPER. Could you speak to the different antiandrogens examined in these studies? How do you approach selection?

These agents all have similar efficacy and clinical activity; however, it’s important to note that they have not been compared head-to-head. The curves and patient populations are strikingly similar. Darolutamide, however, does not cross the blood–brain barrier as readily as the other agents.

No one has made this argument but, at some point, we might worry about not getting an agent across the blood–brain barrier. We never used to see brain metastases in prostate cancer; but due to the way we treat patients now and the fact that we're much better at blocking the androgen access, we're seeing tumors do strange things.

Ultimately, to date, we can use any of these agents, although darolutamide may be preferable in certain cases. When making decisions, we must also keep the costs of these agents in mind although this is unique to each patient’s insurance.

Does your treatment approach differ if someone has a slowly rising PSA?

The data [with these agents] only apply to patients with a rapid PSA doubling time. As such, if you have someone whose PSA is going up slower than 1 year, then that wasn't the patient population that they looked at. If someone's PSA doubling time is 10.5 months, I'd consider that to be pretty similar. However, if someone's doubling time is 2 years, then that's a different population and we don't know if they can benefit from this approach.

In my practice, I don't immediately put patients on 1 of these agents when their PSA is rising slowly. However, this is a pretty rare population; there aren’t many patients who show no evidence of disease on scans.

Has treatment discontinuation been considered in this disease?

Treatment discontinuation is not something I would consider for this disease, unless a patient cannot tolerate the therapy. In that case, the treatment would have to be discontinued; however, we would then administer a different therapy in its place. Patients need to make these decisions with us.

In the past, there was a hypothesis that intermittent treatment was better than continuous treatment. The idea was, if we give patients continuous ADT, we are selectively benefiting the clones that are androgen resistant; however, this did not turn out to be the case. With this in mind, although no one has considered treatment discontinuation yet, it’s probably a bad idea.

What are some of the ongoing research efforts being made with these agents?

The early use of therapy has been a common theme over the years. For example, we use chemotherapy early on. The big question right now in metastatic disease and early castration-sensitive disease is, should we use chemotherapy in combination with other drugs such as abiraterone acetate [Zytiga]? Several studies are evaluating the combination; however, we have not seen any results yet.

Another question is, can we somehow use these agents in the neoadjuvant setting to make surgery for high-risk patients better? Those studies are suggestive, but nothing definitive has been shown yet.

With all of the technological advances made in recent years, do you find that it is harder to identify someone who has nonmetastatic disease?

With the use of better scanning techniques, we are seeing things in patients whom we would normally [determine] to have nonmetastatic disease. Now, we don’t know where they fit and how we should treat them. Unfortunately, we won’t have an answer until a study is done or until treatments become more advanced. In these cases, I tell my patients what I would have told them with the old scans. After describing the potential benefits and trade-offs, I let them have a say in what should be done next.