SAN FRANCISCO-Apalutamide, a nonsteroidal antiandrogen agent under development for the treatment of prostate cancer, is an effective treatment for men with non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk for developing metastatic disease, according to a new study.
Men who received apalutamide had a 72 percent lower risk of metastasis or death than those who received placebo in the phase III SPARTAN trial. These findings may be relevant to about 100,000 men in the U.S., according to the researchers.
"Until this trial, there have been no drugs proven to benefit men with non-metastatic prostate cancer that has progressed despite standard hormonal therapy. These results show that apalutamide made a significant difference in prolonging the time before the development of metastasis," said lead author Eric J. Small, MD, Professor of Medicine at the University of California San Francisco, at a presscast ahead of the 2018 Genitourinary Cancers Symposium (Abstract 161).
The study results were also published in the New England Journal of Medicine (2018; doi:10.1056/NEJMoa1715546).
Many men with prostate cancer recurrence following local treatment with surgery or radiation therapy are treated with androgen deprivation therapy (ADT). But many prostate cancer patients subsequently develop resistance to ADT.
Metastatic castration-resistant prostate cancer is a uniformly fatal disease, with a median survival of about 2.5 years. Metastatic castration-resistant prostate cancer can develop from metastatic hormone-sensitive prostate cancer or nmCRPC that has developed resistance to ADT, Small noted.
Some physicians have advocated watchful waiting for patients with nmCRPC; however, men whose prostate-specific antigen (PSA) score is rapidly rising while on ADT (with a PSA doubling time of less than 8-10 months) are at a significantly increased risk of developing metastases or death.
Recently announced as the first FDA-approved treatment for nmCRPC, apalutamide is a next-generation competitive inhibitor of the androgen receptor for the treatment of patients with prostate cancer. It prevents binding of androgens to the androgen receptor, prevents translocation of the androgen receptor to the nucleus, and impedes androgen receptor-mediated DNA transcription, Small said.
SPARTAN Study Results
The SPARTAN trial, conducted at 332 institutions worldwide, enrolled 1,207 men with nmCRPC that had stopped responding to ADT and who were at high risk of metastasis based on a PSA doubling time of 10 months or less. The men were randomly assigned to receive oral apalutamide 240 mg or placebo daily, added to ongoing ADT. At the time of development of metastases, patients were treated with standard second therapies at their physician's discretion and had an option to receive on-study abiraterone acetate and prednisone.
The median PSA doubling time at study entry was approximately 4.5 months in both the apalutamide and placebo groups. Apalutamide decreased the risk of metastasis and death by 72 percent compared with placebo and significantly prolonged the median metastasis-free survival by more than 2 years (40.5 months in the apalutamide group vs. 16.2 months in the placebo group).
At an interim analysis, there was a trend favoring improved overall survival for men receiving apalutamide, although the difference was not statistically significant. Following the analysis of metastasis-free survival, study treatment was unblinded in July 2017 following the recommendations of an independent data monitoring committee, and all patients were offered open-label apalutamide.
At a median follow-up of 20.3 months, 61 percent of patients in the apalutamide group and 30 percent of placebo-treated patients were still on treatment.
Apalutamide was well-tolerated with no difference in serious adverse events between apalutamide and placebo groups. Rates of discontinuation due to adverse events were low in both groups, 10.7 percent on apalutamide and 6.3 percent with placebo. Mean baseline patient-reported health-related quality-of-life scores were maintained with treatment with no difference between groups over time.
New Standard of Care
"These data demonstrate that the use of apalutamide prior to the development of metastases clearly benefited patients whose prostate cancer no longer responded to conventional hormonal therapy," Small stated. "It is exciting that there now exists such a well-tolerated agent for this group of high-risk patients for whom no approved therapies currently exist. Overall, these data suggest that apalutamide should be considered as a new standard of care for men with high-risk nmCRPC."
The researchers hope to identify those patients who benefited the most from apalutamide by analyzing molecular and circulating markers from blood samples. They also will look in greater depth at patient-reported outcomes that evaluate the trial success or failure from a patient perspective.
"There is a population of men with prostate cancer who have no visible evidence of spread, but who have a rise in their blood markers," stated ASCO Expert Sumanta K. Pal, MD, Associate Clinical Professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, Duarte, Calif. "These patients can have a poor prognosis and, until now, the optimal management of their cancer remained an enigma. These findings suggest there may finally be a treatment that holds real promise for extending their health and their lives."
Pal noted that a related trial, PROSPER, with similar design and results presented at the meeting showed that enzalutamide significantly delayed time to disease in men with nmCRPC.
However, Pal noted that "the disease state of nmCRPC with rising PSA may be a shrinking population. Improvements to detect metastatic disease with PET scans may detect disease spread earlier and change our disease strategy."
Mark L. Fuerst is a contributing writer.