Mark J. Mann, MD
There have not been designated novel treatment options for patients with nonmetastatic castration-resistant prostate cancer (CRPC) until very recently, explains Mark J. Mann, MD.
According to the American Urological Association (AUA) guidelines, patients with nonmetastatic CRPC should be observed with continued androgen deprivation therapy (ADT). Alternative treatment can include first-generation antiandrogens, such as flutamide, bicalutamide (Casodex), and nilutamide (Nilandron), or first-generation androgen synthesis inhibitors, such as ketoconazole plus a steroid. Clinicians should not offer systemic chemotherapy or immunotherapy to these patients, according to these guidelines.1
Due to the stagnant treatment landscape, the February 2018 FDA approval of apalutamide (Erleada) for patients with nonmetastatic CRPC has been exciting for both patients and treating physicians. The approval is based the results of the phase III SPARTAN trial, in which apalutamide reduced the risk of metastasis or death by 72% in this patient population. The median metastasis-free survival (MFS) was 40.5 months in the apalutamide arm versus 16.2 months in the placebo arm (HR, 0.28; 95% CI, 0.23-0.35; P
<.0001). At a median follow-up of 20.3 months, 61% of the apalutamide arm remained on treatment compared with 30% of patients receiving placebo. An interim overall survival (OS) analysis of 24% of events revealed a trend favoring apalutamide.2
In March 2018, the FDA granted a priority review to a supplemental new drug application for enzalutamide (Xtandi) for the treatment of men with nonmetastatic CRPC. The decision was based on phase III data of the PROSPER trial, in which the combination of enzalutamide plus ADT reduced the risk of metastases or death by 71% versus ADT alone.3
Additionally, the median MFS was 36.6 months with enzalutamide plus ADT versus 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35; P
In an interview during the 2018 OncLive®
State of the Science Summit™ on Prostate Cancer, Mann, an assistant professor of urology at Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, discussed the developing treatment landscape for patients with nonmetastatic CRPC.
OncLive®: Please provide an overview of your lecture on the treatment of nonmetastatic CRPC.
: The definition of nonmetastatic CRPC is a patient with a prostate-specific antigen (PSA) that is 2 over the nadir, or a 25% increase from the nadir while the testosterone is still repressed. The next part of the diagnosis is determining whether it is metastatic. That is done with a CT scan and a bone scan, which are standard, but there are new imaging modalities that are starting to come into play, specifically PET scans.
The next step in surveillance is to make sure the patient [has] nonmetastatic disease. We discussed the AUA recommendations for treatment, or rather the lack of treatment, and the indication where we will then progress to more advanced treatments. I also discussed the latest ASCO publicized studies, such as enzalutamide in the PROSPER trial and apalutamide in the SPARTAN study.
Can you discuss the current AUA guidelines?
The current AUA guidelines for nonmetastatic CRPC is to continue with ADT. If the patients are not willing or do not accept those recommendations, then you can offer them a first-generation antiandrogen, such as bicalutamide, or a first-generation androgen synthesis inhibitor along with a steroid. The guidelines also are clear that they do not recommend chemotherapy or immunotherapy in those patients.
Can you speak to the importance of the apalutamide approval and the background of the study?
The SPARTAN trial was for nonmetastatic CRPC, where patients could have been clinically N0 or N1, which indicates that they may have had more advanced disease in that trial. This trial randomized patients to apalutamide with ADT or ADT alone. They found that OS endpoints were not met and the time of progression to metastatic disease was approximately 44 months compared with less than 1.5 years in the ADT group alone.
Apalutamide has also recently been added to the National Comprehensive Cancer Network guidelines. Can you discuss this?
Apalutamide is an interesting drug in that it is a nextgeneration androgen receptor inhibitor. It targets the receptor, the signaling cascade, and DNA, binding with fewer central nervous system toxicities.
What are some of the challenges that remain with apalutamide?
It will be interesting to see its efficacy when broken down into racial differentials to determine how effective it is in patients with different ethnicities. Furthermore, it will be interesting to see how it affects the cascade of drugs that typically follows and how it plays into that role.