<p>Although treatment options for high-risk localized prostate cancer have expanded, patient outcomes remain suboptimal, with many patients developing metastatic disease with the use of the current treatment modalities. These patients may benefit from therapeutic strategies combining ARPIs with radiation therapy and ADT.</p>

Although there is no one agreed-upon definition for high-risk localized prostate cancer, we can use the same definition that was used in the STAMPEDE trial. This study evaluated the intensification of ADT with abiraterone and led to the US Food and Drug Administration (FDA) approval of abiraterone for high-risk localized prostate cancer. The definition that was used in STAMPEDE was patients with at least 2 of the following: a T stage of 3 or more, a Gleason score of 8 or more, and/or a prostate-specific antigen (PSA) level of at least 40 ng/mL. For busy practitioners who may not see these types of patients very often, I tell my colleagues that the presence of 1 or more of the following features can be considered high-risk disease and that they should consider ADT intensification in these patients: a T stage of 3 or more, a Gleason score of 8 or more, and/or a PSA level of 20 ng/mL or more.

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Multiple ongoing, phase 3 clinical trials are evaluating the use of ARPIs in combination with radiation therapy and ADT in patients with high-risk localized prostate cancer. We have the DASL-HiCaP trial of darolutamide in the salvage radiation therapy setting and the GUIDANCE trial of darolutamide in the primary radiation therapy setting. GUIDANCE is similar to the STAMPEDE trial but with darolutamide rather than abiraterone, and darolutamide will be given based on the patient’s Decipher score. And then we have the ENZARAD trial, which is evaluating the addition of enzalutamide vs older-generation antiandrogen therapy such as bicalutamide to primary or definitive radiation therapy and ADT in patients with high-risk localized prostate cancer. And, finally, in the ATLAS trial, patients with high-risk localized or locally advanced prostate cancer are receiving primary radiation therapy and a GnRH agonist with or without apalutamide. So, the field is likely going to expand beyond the use of abiraterone.

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The majority of the side effects of ADT happen because of a patient’s testosterone level lowering to less than 50 ng/mL, as that is a huge hit to a man’s body—even harder than chemotherapy, in my experience. Hot flashes are one of the most debilitating side effects in men who are receiving ADT plus ARPI therapy and can be addressed, to a large extent, if you remove the ADT.

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GnRH agonists such as leuprolide are associated with a very delayed recovery of serum testosterone once discontinued. On the other hand, for GnRH antagonists such as relugolix, the testosterone recovery can be quicker, as was demonstrated in the HERO trial. So, if a patient is starting ADT plus ARPI and radiation therapy in the localized prostate cancer setting, I am increasingly suggesting that GnRH antagonists be used in conjunction with ARPI therapy because these patients are receiving ADT for a short duration in conjunction with radiation therapy, and they deserve to have a full recovery of their testosterone after the completion of their therapy. From that perspective, GnRH antagonists are very important to bring up when we discuss limited-duration ADT with patients.