Dr. Cookson began by emphasizing that, among the nearly 250,000 new cases of prostate cancer annually in the US, 15-40% will develop biochemical recurrence within 10 years of treatment and that the median time to biochemical recurrence (BCR) is 2-3 years. Further, more than 34,000 men will die of prostate cancer in the US this year. Dr. Cookson suggested that nmCRPC may represent a “window of opportunity, that closes quickly” to treat patients when their lower tumor burden may allow a better or more durable response. Further, delaying the development of metastasis is clinically relevant given its association with both morbidity and survival.
Recently, three novel second-generation anti-androgens (apalutamide, darolutamide, and enzalutamide) have been approved in this disease space. Functionally, these agents serve to prevent the binding of the androgen receptor to androgens, to prevent the translocation of the androgen receptor to the nuclear, and to interfere with the binding of the androgen receptor to DNA.
Dr. Cookson then cited data from Dr. Smith and colleagues demonstrating that the risk of metastasis increases with shortening PSA doubling time in patients with nmCRPC.
He then highlighted recent guidelines on nmCRPC. The guidelines emphasize that these patients should have PSA monitoring every 3 to 6 months with the calculation of PSA doubling time beginning with the development of CRPC. Further, conventional imaging should be performed every 6 to 12 months to assess for the development of metastatic disease. In those with no evidence of metastatic disease, treatment with apalutamide, darolutamide, or enzalutamide can be considered for those with PSA doubling times less than 10 months. For those with longer doubling times, observation is recommended. Notably, chemotherapy and immunotherapy should not be given in this setting outside of a clinical trial.
Looking back over the disease trajectory, Dr. Cookson highlighted that this disease space had no approved therapies until 2018. The SPARTAN trial, initially published in 2018, demonstrated improved metastasis-free survival for patients receiving apalutamide in high-risk nmCRPC. This study used a 2:1 randomization scheme with stratification based on PSA doubling time, nodal involvement, and use of bone targeting agents.
Early use of apalutamide in the nmCRPC space was associated with significantly prolonged metastasis-free survival (HR 0.28, 95% CI 0.23-0.35). This translated into a 24.3-month median improvement in metastasis-free survival. With longer follow-up, an overall survival benefit has been seen (difference in median OS of 14 months). Further, treatment was relatively well tolerated with a marginally increased rate of serious adverse events (24.8% vs 23.1% with placebo). Additionally, health-related quality of life was preserved.
Dr. Cookson then discussed the similarly designed ARAMIS study examining darolutamide. This study similarly showed a benefit to the use of androgen targeting in nmCRPC with a hazard ratio of 0.41 (95% CI 0.34-0.50) for metastasis-free survival, translating into a 22-month absolute improvement in median MFS. Again, with longer follow-up, an overall survival benefit was seen. Further, darolutamide was well tolerated, and most measured health-related quality of life favoured daroluatmide compared to placebo with statistically significant benefits in bowel and urinary symptoms. Additionally, use of darolutamide in nmCRPC delayed initiation of first cytotoxic chemotherapy and the first symptomatic skeletal-related event.
Finally, Dr. Cookson discussed the PROSPER study examining enzalutamide. This study employed a comparable study design to the others. Again, the use of enzalutamide was associated with significantly improved metastasis-free survival (HR 0.29, 95% CI 0.24-0.36), translating to an absolute benefit of 21.9 months in median MFS. Additionally, as with the other agents, longer follow-up showed improvements in overall survival with a difference in median OS of 11.7 months. As with the others, enzalutamide was relatively well tolerated in this patient population and was associated with stable to improved quality of life measures.
In closing, Dr. Cookson emphasized that the FDA approval of these agents is not restricted by PSA doubling time though guidelines recommend their use in men with PSA doubling times of 10 months or less with observation for those with longer doubling times.
Presented by: Michael S. Cookson, MD, MMHC, Professor, and Chairman, Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Written by: Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto Contact: @WallisCJD on Twitter during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.