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"Therapeutic layering... is now becoming commonplace in the initial treatment of newly diagnosed metastatic prostate cancer," writes Leonard G. Gomella, MD.
Dr. Gomella, a member of the Urology Times Editorial Council, is chairman of the department of urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia.
Since the pioneering work of Huggins and Hodges was first published nearly 80 years ago in Cancer Research (1941; 1:293–7), the management of metastatic prostate cancer has relied on primary androgen deprivation therapy (ADT). Reducing the circulating levels of androgens is the foundation for all treatments, from newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) through the late stages of metastatic castration-resistant prostate cancer (mCRPC). While ADT usually slows prostate cancer progression, metastatic prostate cancer remains a fatal disease in need of improved therapies.
The phase III ARCHES trial evaluated enzalutamide (XTANDI) plus ADT in men with mHSPC. The study met its primary endpoint of improving radiographic progression-free survival versus ADT alone. ARCHES is another example of the trend in combining agents to improve outcomes, a concept known as “therapeutic layering.”
Therapeutic layering, first described in the treatment of mCRPC, adds one or more agents onto an existing therapy (Urology 2017; 104:150-9). The concept is now becoming commonplace in the initial treatment of newly diagnosed metastatic prostate cancer.
Other recent examples of therapeutic layering in which agents are added to ADT in mHSPC include the CHAARTED trial (adding docetaxel), the LATITUDE trial (adding abiraterone [ZYTIGA]/prednisone), and the TITAN trial (adding apalutamide [Erleada]). Results from both CHAARTED and LATITUDE demonstrated improved overall survival with the combination therapy. Preliminary results from TITAN have also shown improved survival. ARCHES has shown the benefit of layering enzalutamide with ADT.
The recent trials using therapeutic layering are redefining how initial mHSPC is managed. Historically, the addition of nonsteroidal antiandrogens (eg, flutamide, bicalutamide) to ADT regimens represented the first therapeutic layering attempts, but only minor improvements in long-term outcome were seen with this combined androgen blockade (CAB) approach. CAB outcomes were inferior to those of recent trials that support the combined use of ADT with chemotherapy or next-generation androgen receptor pathway blockers in mHSPC.
Docetaxel and abiraterone are now part of mHSPC guidelines such as those from the National Comprehensive Cancer Network. With the likely approval of enzalutamide based on the ARCHES trial, we will have one more agent available to perform therapeutic layering to improve outcomes in men with newly diagnosed metastatic prostate cancer.