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"While much work is still to be done, we have excellent evidence that there is a beneficial class-like effect for the androgen inhibitors enzalutamide, apalutamide, and darolutamide used within the current definition of men with M0 CPRPC," write Michael Cookson, MD, and Tony Rodriguez, MD.
Michael Cookson, MD
Tony Rodriguez, MD
Dr. Cookson is professor and chairman of urology and Dr. Rodriguez is a urologic oncology fellow at the University of Oklahoma, Oklahoma City. Disclosure: Dr. Cookson is a consultant to Astellas Pharma US, Inc. and serves on the advisory board of Bayer Healthcare Pharmaceuticals, Inc. and Ferring Pharmaceuticals, Inc.
The landscape for management of men with advanced prostate cancer continues to evolve. This is true for patients with newly diagnosed metastatic prostate cancer and those who have progressed to castration resistance.
Recently, Fazizi et al reported the results of the ARAMIS trial (N Engl J Med 2019; 380:1235-46). This study adds additional level 1 evidence for improved outcomes in men with nonmetastatic (M0) castrate-resistant prostate cancer (CRPC) using darolutamide (Nubeqa), a new antiandrogen.
Importantly, in this study, men with M0 CRPC at high risk for development of metastases were continued on their traditional castration and then randomized to either darolutamide or placebo. Similar to the earlier PROSPER and SPARTAN studies of enzalutamide (XTANDI) and apalutamide (Erleada), respectively, the primary endpoint of ARAMIS was metastasis-free survival (MFS) (N Engl J Med 2018; 378:1408-18; N Engl J Med 2018; 378:2465-74). In all three trials, all M0 CRPC patients were at high risk for the development of metastases due to the eligibility requirement of a PSA doubling time of 10 months or less.
Additionally, assessment of metastatic disease was based on conventional CT or MRI imaging and bone scan. In ARAMIS, the study met its primary endpoint with MFS increasing by 22 months, corresponding to a significant relative risk reduction of 59% (95% CI: 0.66 to 0.50; p<.001). This is consistent with the magnitude of the benefit observed in the PROSPER and SPARTAN trials.
Darolutamide is a nonsteroidal antiandrogen with novel chemical structure limiting blood-brain barrier penetrance (J Clin Oncol 2019; 37 [suppl]:156). Accordingly, there were no differences in CNS-related adverse events, including seizures, dizziness, falls, fractures, or cognitive impairment compared to placebo. More patients in the study arm experienced mild fatigue, and quality of life was no different between groups; this is an important consideration in the mostly asymptomatic patient population with M0 CRPC.
The ARAMIS authors note that darolutamide was associated with “fewer adverse events than those reported in the respective phase III trials.” While there is biologic plausibility for a real difference in side effects among these agents, we would caution against making conclusions about comparative safety without head-to-head studies.
At press time, darolutamide was approved by the FDA and became a third option for the treatment of M0 CRPC. This follows the established pattern of expanding indications for therapies by instituting treatment at earlier disease states.
How indications might change with the redefining of disease states being ushered in by advanced radiotracers is a coming challenge. A recent study of prostate-specific membrane antigen-targeted imaging in patients with recurrent prostate cancer found metastases in >85% of patients with PSA >2.0 ng/mL, which was a minimum inclusion value for ARAMIS (JAMA Oncol 2019; 5:856-63). This further complicates the problem of appropriate sequencing of all available antiandrogens. In addition, we are learning that incorporation of germline and somatic genetic information may better inform treatment decisions.
While much work is still to be done, we have excellent evidence that there is a beneficial class-like effect for the androgen inhibitors enzalutamide, apalutamide, and darolutamide used within the current definition of men with M0 CPRPC.