Androgen deprivation therapy (ADT) has served as the backbone of treatment for advanced prostate cancer (APC) since Charles Huggins’ discovery of its inhibitory effect on prostate cancer in 1941. With recent FDA (Food and Drug Administration) approvals of novel hormonal therapies (NHTs) for androgen blockade and newly published data supporting combination therapies, treating APC is now more complex. In this rapidly evolving landscape, urologists must stay apprised of advances in ADT to appropriately manage APC patients.

Table. Summary of Key Randomized Trials Involving Androgen Deprivation Therapy Published Since 2020

Advancements in ADT for APC have been made across the disease spectrum. Multiple randomized trials have demonstrated superior efficacy of combination ADT compared with monotherapy in different disease states, and the field continues to move toward treatment intensification (see Table). In patients with biochemical recurrence, the recent 2020 AUA/American Society for Radiation Oncology/Society of Urologic Oncology APC guidelines recommend against routine initiation of ADT. In metastatic hormone-sensitive prostate cancer (mHSPC), recently published data from the PEACE-1¹ and ARASENS² have paved the way for triplet therapy in select patients. Among patients with nonmetastatic castration-resistant prostate cancer and metastatic castration resistant prostate cancer, use of combination NHT and gonadotropin releasing hormone (GnRH) agonist/antagonists remains critical, but novel treatment options such as PARP (poly [ADP-ribose] polymerase) inhibitors and radioligand-based therapies along with the shift toward use of NHT in earlier disease states leaves numerous unanswered questions about which agents to use and when.

PEACE-1 was an international multicenter, phase 3 trial of 1,173 men with de novo mHSPC who were randomized to standard of care (SOC) with ADT alone or with docetaxel, SOC plus radiotherapy, SOC plus abiraterone, or SOC plus radiotherapy plus abiraterone. Patients receiving triplet therapy (ADT+abiraterone+docetaxel) had a 2.5-year radiographic progression-free survival benefit (HR 0.54, 95% CI 0.46-0.64, P < .0001) and improved overall survival (HR 0.75, 95% CI 0.59-0.95, P = .017) compared to ADT+docetaxel alone.

Similarly, ARASENS was an international multicenter, phase 3 trial of 1,306 men with mHSPC treated with ADT and docetaxel who were randomized to receive darolutamide or placebo. Compared to placebo, those who received darolutamide had 32.5% lower risk of death (HR 0.68; 95% CI 0.57-0.80; P < .001). Darolutamide was also associated with longer time to castration-resistant prostate cancer, longer time to progression, longer symptomatic skeletal event–free survival, and longer time to initiation of subsequent therapy (all P ≤ .01) with a similar adverse event profile to the placebo group.

PEACE-1 and ARASENS both provide strong evidence for treatment intensification in select men with mHSPC. The new AUA APC guidelines and these recent trials have virtually eliminated the routine role for ADT monotherapy. Which agents, and in what combination and sequence, provide optimal outcomes remains unknown at present but we anticipate more answers as additional data are published.

While most urologists are familiar with injectable GnRH agonists (eg, leuprolide) and antagonists (eg, degarelix), the introduction of relugolix, the first oral GnRH antagonist, provides a new treatment option. Relugolix was FDA approved for use in APC in December 2020 based on the results of the HERO trial,³ a phase 3 randomized, controlled trial that compared relugolix and leuprolide in APC patients. Relugolix was superior to leuprolide in several key endpoints including sustained testosterone (T) suppression through 48 weeks (96.7% relugolix vs 88.8% leuprolide, P < .001), probability of castrate T on day 4 (56% relugolix vs 0% leuprolide, P < .001), and >50% reduction in PSA at day 15 (79.4% relugolix vs 19.8% leuprolide, P < .001). Notably, although cardiovascular events were low overall, the incidence of major adverse cardiovascular events (MACE) was significantly lower in the relugolix group compared to leuprolide (2.9% vs 6.2%, HR 0.46, 95% CI 0.24-0.88).

The potential benefits of an oral GnRH antagonist include improved patient acceptance due to avoidance of injection site reactions (40% incidence with degarelix⁴), patient preference for oral formulations, and flexible administration schedule facilitating intermittent ADT due to its once-daily administration and rapid T suppression and recovery. While adherence to relugolix in the HERO study was excellent (99%), whether this level of adherence can be maintained in a real-world setting is unknown. Cost remains a significant concern with annual out-of-pocket costs for U.S. Medicare beneficiaries estimated to be $3,731 for relugolix and $745 for leuprolide.⁵ Despite these concerns, relugolix represents an exciting new option for some patients with APC.

Aside from the introduction of novel agents and expanding indications for existing ADT, there has been significant recent progress in the recognition and study of the adverse effects of ADT including changes in cardiovascular, bone, endocrine MACE, and cognitive health. While a link between ADT and risk of MACE has been drawn for decades, how significant this risk is, which agents have the lowest risk, and how to manage this risk remains controversial.⁶ Observational data have shown that ADT is associated with increased risk for MACE⁷ and randomized trial data pooled post hoc have suggested lower risk of MACE for GnRH antagonists compared to agonists.⁸

The PRONOUNCE trial was a recently active international multicenter randomized trial designed to evaluate the relative cardiovascular safety of GnRH antagonists compared with agonists.⁹ Although the study was terminated prematurely due to poor recruitment and low event rate, no difference was observed in MACE at 1 year between degarelix and leuprolide (5.5% degarelix vs 4.1% leuprolide; HR 1.28, 95% CI 0.59-2.79). Given a lack of power and early termination of the study, the differential impact of GnRH agonists and antagonists on cardiovascular risk remains unknown. While some aspects of the cardiovascular impact of ADT remain controversial, there is broad consensus that rigorous cardiovascular risk factor control is imperative and a collaborative multidisciplinary approach is critical for patients on long-term ADT to mitigate risk.

APC remains a rapidly changing field with multiple recent advancements. Urologists should be aware of new agents available for ADT and the varying potential clinical scenarios for their use. It is increasingly important for urologists to work in collaboration with a multidisciplinary team including primary care physicians, cardiologists, medical oncologists, and radiation oncologists for optimal management of patients with APC.