Clinical Pearls & Morning Reports
Metastatic prostate cancer can be broadly divided into two groups: disease that has not been treated with androgen deprivation and disease that is resistant to such therapy. Read the latest NEJM Review Article here.
Q: What new treatments may augment androgen-deprivation therapy alone for newly diagnosed metastatic prostate cancer?
A: For men with an initial diagnosis of metastatic prostate cancer, continuous androgen-deprivation therapy represented the standard of care from 1941 until 2015, when two trials showed that androgen-deprivation therapy combined with six courses of docetaxel improved survival. The combination of androgen-deprivation therapy and abiraterone with prednisone represents a new standard of care for metastatic disease that is based on data from the CHAARTED and STAMPEDE trials. Though the effectiveness of abiraterone and that of docetaxel in prolonging survival appear to be equivalent, clear distinctions are noted in the duration of therapy used in previous trials for patients with an initial diagnosis of metastatic disease. The duration and cost of treatment may influence clinical decision making. Data from studies determining whether contemporaneous administration of androgen-deprivation therapy, docetaxel, and abiraterone–prednisone is superior to serial administration of these agents are awaited.
Table 1. (10.1056/NEJMra1701695/T1) Practice-Changing Trials of Treatments for Metastatic Prostate Cancer That Improve Survival.
Q: Has there been progress in the treatment of metastatic, castration-resistant prostate cancer in recent years?
A: Clinical progress in treating metastatic, castration-resistant prostate cancer during the past 7 years has been remarkable. Pivotal trials resulting in an overall survival benefit have led to regulatory approval for two hormonal therapies, an additional taxane, a bone-targeted and alpha-emitting radionuclide, and an immunotherapy. Two new hormonal agents, abiraterone and enzalutamide, have had the largest effect on castration-resistant prostate cancer.
A: Genomic aberrations in metastatic, castration-resistant prostate cancer may be similar to or distinct from genomic alterations in primary prostate tumors that have not been treated with androgen deprivation. The most common alterations in patients with metastatic disease involve the androgen receptor (in >60% of patients), but p53 mutations or deletions are also common. Deleterious DNA-repair aberrations in genes, including BRCA2, ATM, BRCA1, PALB2, and RAD51D, occur in 20 to 25% of patients. Defective mismatch repair has also been reported, and this may be missed by targeted exome or exon sequencing. The use of advanced genomic analysis is now feasible to a greater extent than ever before. Whether its use improves treatment decisions is not yet clear.
A: Optimal sequencing of the various agents is currently unknown. Furthermore, despite a rationale for combination therapy (which is typically used for most cancers), no large, randomized trials testing combination therapy for advanced prostate cancer have been reported to date. Though newer studies indicate that a variety of potentially actionable genetic alterations can be detected in prostate cancer, no therapy targeting these alterations has yet been shown to have a clinical benefit. Novel forms of immunotherapy, especially PD-1 inhibitors, are active in a variety of cancers, especially those with high mutational frequencies. Prostate cancer has a lower mutational burden, and the use of PD-1 inhibitors for prostate cancer remains experimental (though the activity of these agents may be higher in tumors with defective mismatch repair than in tumors with other genetic alterations). Thus, advanced genetics and immunology, two major drivers of progress in oncology, are not routinely incorporated into the care of patients with prostate cancer.