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ADT Considerations for CSPC
Considerations With Androgen-Deprivation Therapy for Castration-Sensitive Prostate Cancer

Released: October 02, 2023

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Key Takeaways
  • For patients with CSPC experiencing biochemical recurrence without metastasis, immediate ADT is associated with no survival benefit and worse quality of life.
  • ADT should be given to all patients with metastatic CSPC as part of a doublet or triplet therapy.
  • Data from the HERO trial suggest that the GnRH antagonist relugolix has fewer cardiovascular adverse events than leuprolide, particularly for patients with a history of major adverse cardiovascular events.

In this commentary derived from a recent live presentation, Daniel Saltzstein, MD, a urologist who specializes in prostate cancer, summarizes key points to consider in clinical practice today about androgen-deprivation therapy (ADT) in the optimal care of patients with castration-sensitive prostate cancer (CSPC) across the spectrum of disease.

Androgen Suppression
CSPC is androgen dependent for growth and survival, with the androgen receptor (AR) being highly expressed in tumor cells. We thus control disease by manipulating testosterone levels or how testosterone binds to the AR.

ADT reduces circulating levels of androgens. Standard ADT agents act at the pituitary level as either gonadotropin-releasing hormone (GnRH) agonists or antagonists. GnRH agonists such as goserelin and leuprolide cause an initial overstimulation of the GnRH receptor that leads to increased production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as a “flare” in testosterone levels. However, chronic administration suppresses LH and, consequently, decreases testosterone levels. GnRH antagonists such as degarelix and relugolix directly inhibit the release of LH and FSH, causing immediate LH suppression and castration (testosterone <50 ng/dL) without a testosterone flare. Later in this commentary, I will discuss key factors when deciding between GnRH agonists vs antagonists.

By contrast, AR signaling inhibitors—such as abiraterone, apalutamide, darolutamide, and enzalutamide—prevent testosterone from binding to the AR, as well as nuclear translocation of the AR.

When to Use ADT for Nonmetastatic CSPC/Biochemical Recurrence
Patients with nonmetastatic CSPC can experience biochemical recurrence—a phenomenon where prostate-specific antigen (PSA) levels are rising despite castrate levels of testosterone—in the absence of metastatic disease. Current National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA) guideline recommendations are to not routinely start ADT in this setting. Instead, you should first exhaust all forms of local therapy (eg, surgery, radiation) and then offer observation or a clinical trial. A retrospective analysis reported no survival benefit for those immediately initiating ADT prior to metastatic disease vs delaying ADT until after identifying metastatic disease. Furthermore, quality of life was worse in patients who immediately initiated ADT vs those who delayed ADT.

However, if a patient is very anxious about their disease and chooses to initiate ADT prior to detection of metastatic disease, it is recommended to offer intermittent rather than continuous ADT. A phase III noninferiority trial demonstrated no difference in disease-specific survival between patients receiving continuous vs intermittent ADT, and those receiving intermittent ADT had better quality of life with fewer hot flashes, fewer sexual adverse events, and less urinary urgency.

Phase III clinical trials also are evaluating early ADT in combination with a novel hormonal agent (ie, abiraterone, enzalutamide, apalutamide, or darolutamide) in patients with nonmetastatic CSPC and high-risk biochemical recurrence after definitive therapy who have a rapid PSA doubling time and may benefit from intensified therapy, with enzalutamide recently being granted priority review by the FDA in this setting.

When to Use ADT for Metastatic CSPC
All patients with metastatic CSPC should receive ADT, with the addition of other modalities depending on patient-specific factors and the extent of disease. For those with oligometastatic disease, which is a unique clinical state characterized by isolated metastases amenable to focal ablative therapy, ADT plus radiation therapy is recommended. Patients with low-volume disease are recommended to receive doublet therapy with ADT plus an AR antagonist (abiraterone, apalutamide, or enzalutamide). For chemotherapy-fit patients with high-volume disease, this regimen can be intensified to triplet therapy comprising ADT, docetaxel, and either abiraterone/prednisone or darolutamide.

Considerations for ADT Use in the Management of CSPC

Factors Influencing Choice of ADT
Those who treat patients with CSPC must now decide between orchiectomy or—more commonly—GnRH agonists vs antagonists as ADT in their patients with CSPC, a decision that is based on several factors. The efficacy and speed in achieving castration needs to be considered. As discussed above, GnRH antagonists act immediately, whereas the action of GnRH agonists is delayed. The route of administration of these drugs also varies. For example, does the patient prefer a daily pill, an injection, or a small implant under the skin? For the latter, how often is the agent administered—every month, every 3 months, or every 6 months—and does the patient have straightforward access to the clinic? Cost is also a big factor in how we decide between options. Last but not least, safety is a critical factor in decisions around ADT, which is associated with metabolic, cardiovascular, musculoskeletal, cognitive, and neuropsychiatric issues, as well as sexual dysfunction.

Prevention and Management of Adverse Events With ADT  
With ADT, it is not as simple as starting a patient on a medication and keeping an eye on the adverse events—we need to be proactive to avoid potential comorbidities.

For patients starting ADT, the NCCN and AUA guidelines recommend that we discuss the risk of osteoporosis, diabetes, and cardiovascular events. Because ADT lowers estrogen, which is bone protective, we must consider osteoporosis prevention and recommend a bone-protective agent, vitamin D, and calcium. The risk of experiencing cardiovascular adverse events varies depending on the ADT agent and patient’s history. Among patients enrolled in the phase III HERO trial, those with a history of major adverse cardiovascular events (MACE) had a higher rate of MACE with leuprolide vs relugolix (17.8% vs 3.6%, respectively). Among those with no history of MACE, the incidence of MACE was lower in both arms, although still higher with leuprolide (6.2% vs 2.9% with relugolix). Fatigue is also extremely common with ADT, and we should encourage exercise. Hot flashes, metabolic syndrome, and erectile dysfunction are also common.

To monitor and treat these adverse events appropriately, we must use a multidisciplinary approach involving primary care and a team of specialists when appropriate.

Your Thoughts?
How do you decide between ADT agents for your patients with CSPC? Please answer the polling question and join the conversation by posting a comment.

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