Treating Advanced Prostate Cancer While Reducing the Potential for Adverse Events
A major challenge in the treatment of patients with advanced prostate cancer is balancing the trade-offs between the benefits of treatment and the risks of treatment-related adverse events. For patients with nonmetastatic (M0) castration-resistant prostate cancer (CRPC), the potential for side effects such as fatigue, falls, and fractures is an important consideration.
Q: Now that there are several approved therapies for M0 CRPC, how do you decide which patients might benefit from these therapies, and what are the risk-benefit considerations?
Ken and Donna Derr – Chevron Distinguished Professor
“If you have a patient who is hormone refractory but has a prolonged PSA doubling time, you may decide to closely monitor rather than to treat and risk additional treatment-related adverse events.”
The time frame between diagnosis, initial treatment, and subsequent prostate cancer progression and treatment often spans over many years. Most men with advanced prostate cancer were initially thought to have clinically localized disease, were treated, and then failed. In the castration-resistant setting, they have failed again—so many of these patients have borne the side effects of various interventions for many years. The risk-benefit analysis is paramount in all stages of disease. Adverse events of hormonal therapy, such as cognitive issues, cardiovascular toxicity, falls, and bone mineral loss, frequently become major issues over time. When considering the need for additional therapy, profiling the patient (eg, using imaging, disease volume, and prostate-specific antigen [PSA] kinetics) provides a good indication of who might be at risk of overt metastatic disease and require immediate treatment and who might be offered continued surveillance. If you have a patient who has no overt evidence of metastases, but whose PSA is rising despite androgen deprivation (ie, hormone refractory) but has a prolonged PSA doubling time, you may decide to closely monitor rather than to treat and risk additional treatment-related adverse events. We now have 3 anti-androgens to use in the M0 CRPC space: apalutamide, enzalutamide, and darolutamide. From my own perspective, darolutamide is interesting in this regard in that, biochemically, it is distinct from enzalutamide and apalutamide. The issue of blood-brain barrier penetration is of interest to me, as darolutamide may have a lower propensity to cross the blood-brain barrier, and this property may be a valuable asset in certain patient populations. Thus, darolutamide may give you a good outcome with, perhaps, fewer toxic events, but, clearly, all patients are at risk for toxicity from any treatment, and, of course, our goal is to minimize that risk.
Chief Medical Science Officer, Sema4
“As relates to tolerability, we might now have an androgen receptor–targeted therapy that might have a more favorable side-effect profile than other available therapies. Clinicians and patients, alike, are quite interested in this possibility.”
M0 CRPC is a somewhat artificial, or treatment-induced, disease state in which affected patients know that they are becoming resistant to primary hormonal therapy, but they have no symptoms or overt signs of metastasis on conventional imaging. Concerns about this disease state have led to 3 randomized clinical trials in which patients received enzalutamide (PROSPER), apalutamide (SPARTAN), or darolutamide (ARAMIS). Each trial included the subset of patients who have PSA doubling times under 10 months, and I think that is the key group to focus on with respect to minimizing the risks of treatment. The ARAMIS trial of darolutamide in M0 CRPC is the most recent, and it drew a lot of attention because the study group showed no significant differences in grade 3/4 toxicities between darolutamide and placebo. The rationale for this observation was that darolutamide might not cross the blood-brain barrier as compared with enzalutamide and apalutamide. This had been a preclinical finding, and there was great interest to see whether darolutamide may be better tolerated than the other 2 agents. A caveat is that enzalutamide and apalutamide are both tolerated reasonably well by most patients. It is extremely rare to have a patient who has actually had a seizure on any of these drugs. Still, there is a subset of patients who does not do very well with these drugs; they experience significant fatigue or muscle weakness or even falls and fractures, which I think are among the worst side effects we have seen with these therapies. If our clinical experience with darolutamide mimics what we saw in the randomized clinical trial—which I see no reason to doubt—we might now have an androgen receptor–targeted therapy that might have a more favorable side-effect profile than other available therapies. Clinicians and patients, alike, are quite interested in this possibility.
C. E. and Bernadine Laborde Professor of Cancer Research
“I would like to see prospective comparisons between either enzalutamide and darolutamide or apalutamide and darolutamide, but I concur that the adverse event profile for darolutamide reported by Fizazi et al in The New England Journal of Medicine was quite benign.”
Of the 3 aforementioned randomized clinical trials, each has shown that we can provide a significant advantage in metastasis-free survival, a new US Food and Drug Administration (FDA) end point, in patients who received enzalutamide, apalutamide, or darolutamide with continued androgen deprivation therapy, compared with placebo. The darolutamide FDA approval is the most recent. I would like to see prospective comparisons between either enzalutamide and darolutamide or apalutamide and darolutamide, but I concur that the adverse event profile for darolutamide reported by Fizazi et al in The New England Journal of Medicine was quite benign. This was a blinded trial, so it is difficult for me to believe that there are differences between groups that should have been detected but were not. Discontinuation rates were 8.7% in the placebo group and 8.9% in the darolutamide group, and there was no evidence of the falls and fractures risk that you see with some of the other anti-androgens. I thought that these data were quite intriguing. Rash and hypothyroidism have been consistently reported with apalutamide and not with the other 2 agents. I will generally avoid androgen receptor–targeted therapies in a patient with a history of seizures. We ask about seizures before prescribing enzalutamide or apalutamide, and I think that this will be less of a concern with darolutamide. The inclusion criteria for these trials were not similar with respect to previous seizure history, and 12 patients with a history of seizures were treated in the darolutamide arm. Each trial included patients with PSA doubling times under 10 months, which is an important prognostic variable. Not all patients with rapid PSA doubling time are at the same risk of metastasis, and I agree that we should be focusing our efforts on patients who have a high risk for progression to metastasis and a PSA doubling time under 10 months.
Fizazi K, Shore N, Tammela TL, et al; for the ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
Foucher Y, Lorent M, Tessier P, Supiot S, Sébille V, Dantan E. A mini-review of quality of life as an outcome in prostate cancer trials: patient-centered approaches are needed to propose appropriate treatments on behalf of patients. Health Qual Life Outcomes. 2018;16:40-40.
Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474.
Slovin S, Clark W, Carles J, et al. Seizure rates in enzalutamide-treated men with metastatic castration-resistant prostate cancer and risk of seizure: the UPWARD Study. JAMA Oncol. 2018;4(5):702-706.
Smith MR, Saad F, Chowdhury S, et al; for the SPARTAN Investigators Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418.