Using Novel Anti-Androgens in Non-Metastatic CRPC
Tomasz M. Beer, MD
Hospital and Institutional Affiliations
Professor of Medicine and Grover C. Bagby Chair of Prostate Cancer Research at Oregon Health & Science University (OSHU) in Portland, and Chief Medical Officer of the Center for Early Detection Advanced Research at the OHSU Knight Cancer Institute
Question 1. What should be the basis for starting non-metastatic CRPC (nmCRPC) patients on one of the novel anti-androgens?
The studies of enzalutamide and apalutamide used a PSA doubling time of less than 10 months, and that’s a good marker. The shorter the PSA doubling time, the higher the risk of metastases, and so the greater potential benefit of starting treatment early. In the bigger picture, it is important to remember that we are treating asymptomatic individuals, and we’re trying to delay the development of overt metastases that ultimately lead to disease-related morbidity. A discussion with patients about the balance between the risks and costs of the treatment and the risk of metastases and the potential benefits of treatment is always critically important.
In choosing between the available agents, apalutamide and enzalutamide, it’s hard to recommend one over the other based on the 2 studies that established their efficacy. The study results were very similar. The most important thing is choosing which patients should be treated in the first place. I would just focus on patients whose PSA is rising sufficiently quickly, for example, a PSA doubling time of less than 10 months.
Question 2. What would you advise urologists regarding the management of adverse effects that impair QOL?
Attention to side effects is really important because this patient population is almost by definition asymptomatic from the cancer, with no visible cancer on imaging, so the symptoms that these patients experience will be almost entirely due to treatments. Any side effects have the potential to degrade quality of life and need to be looked at very closely. As a practical matter, fatigue is the most common adverse effect. Patients need to be monitored for hypertension. In a small minority of patients, there are some cognitive side effects. With apalutamide, specifically, there may be a skin rash and low but measurable risk of thyroid dysfunction. A urologist needs to get familiar with the side effect burden of these medications.
Question 3. Who should NOT be treated with these medications?
Patients with absolute contraindications, such as those with a history of seizures. Also, patients with severe cardiovascular disease, such as class III or higher heart failure or other unstable cardiac conditions, and frail patients at high risk of falls. The risk of falls roughly doubles with these medications. Falls in the frail elderly can be really devastating. Patients whose PSA is going up very slowly and who have many years ahead of them before they develop metastases may not require treatment. Those patients may be monitored safely and have their treatment initiated at a later date and be spared the side effects and expense of treatment.
Question 4. When men with nmCRPC are placed on one of the novel anti-androgens, what do you think should be the follow-up protocol?
We would recommend an office-based assessment, perhaps a month or 6 weeks into therapy as an initial evaluation to assess side effects and see how patients are doing. Typically, we see patients every 3 months for a physical exam, lab work, and clinical assessment. The frequency of imaging remains a bit unclear. Practically speaking, in someone who is having a PSA response, imaging every 6 to 12 months is probably reasonable, although there is not a consensus around that.
Question 5. If metastatic disease develops, what would be the next step in treatment?
This is a critical and important question. We have almost no data on that. The use of enzalutamide and apalutamide in non-metastatic CRPC is brand new. Thankfully, the drugs are pretty effective. The median time to metastases in the efficacy studies was 3 years or so. The vast majority of patients who are being treated with these drugs are still responding. We don’t have a lot of experience with folks who have progressed yet. The studies that were done did not address adequately the effectiveness of post-progression therapy. For the time being, I prefer docetaxel chemotherapy because abiraterone after enzalutamide in cross-over studies has had a low response rate. But there may be some exceptions to that.