Androgen Deprivation Therapy (ADT) in Advanced Prostate Cancer

GnRH Antagonists vs Agonists: Efficacy and Safety

Both GnRH agonists (e.g. leuprolide, goserelin) and GnRH antagonists (e.g. degarelix, relugolix) are effective in lowering testosterone to castrate levels, achieving high response rates in advanced prostate cancer​ pmc.ncbi.nlm.nih.gov and pmc.ncbi.nlm.nih.gov. GnRH antagonists induce a more rapid testosterone decline without the initial flare (surge in testosterone) seen with agonists​ urologytimes.com and urologytimes.com. For example, degarelix can reach castrate testosterone in ~3 days versus ~28 days with leuprolide​, and in a phase III trial the oral antagonist relugolix suppressed testosterone in 96.7% of patients (vs 88.8% with leuprolide) and reduced PSA equally well pmc.ncbi.nlm.nih.gov.  Crucially, overall efficacy (disease control and time to progression) appears similar between antagonists and agonists​, so both approaches are considered therapeutically equivalent in cancer control.

Safety profiles differ in certain aspects. GnRH agonists cause an initial tumor flare (due to the transient T surge) that can worsen bone pain or urinary obstruction, so anti-androgens are often given at initiation to prevent this​. Antagonists avoid this flare. There is also evidence that GnRH antagonists may carry a lower risk of cardiovascular events than agonists​ pmc.ncbi.nlm.nih.gov​. In a head-to-head trial, relugolix was associated with a 54% relative reduction in major cardiovascular events compared to leuprolide​. This more favorable cardiac profile of antagonists (possibly due to better FSH suppression and lack of T surge) has been noted in multiple analyses​. On the other hand, injectable antagonists like degarelix can cause more local injection-site reactions, whereas agonists (given via depot injection) do not. Overall, GnRH antagonists and agonists are equally effective for ADT, but antagonists offer faster T suppression and may be safer for patients with high cardiovascular risk​. Agonists remain widely used and are well tolerated, but require flare precautions and vigilant metabolic/cardiovascular monitoring​ pubmed.ncbi.nlm.nih.gov

Anti-Androgens: Monotherapy vs Combination Therapy

First-generation anti-androgens (e.g. bicalutamide, flutamide) block the androgen receptor and have been used as monotherapy to avoid the castration side effects of ADT. In non-metastatic disease, studies showed bicalutamide monotherapy can yield similar short-term outcomes to surgical or medical castration​ pmc.ncbi.nlm.nih.gov. For instance, older trials in locally advanced (M0) patients found no significant difference in overall survival or progression between anti-androgen monotherapy and LHRH agonists/orchiectomy​, while patients on bicalutamide had better sexual interest/function and fewer hot flashes​ pubmed.ncbi.nlm.nih.gov. However, monotherapy often causes gynecomastia and breast pain (due to peripheral estrogen rise), which can impact quality of life​ pubmed.ncbi.nlm.nih.gov and pmc.ncbi.nlm.nih.gov. In metastatic prostate cancer, anti-androgen monotherapy is generally inferior to castration. Trials were stopped early due to higher mortality with bicalutamide alone in metastatic patients, establishing that monotherapy should not replace castration in advanced disease​. Instead, combining an anti-androgen with castration (known as combined androgen blockade, CAB) was explored. A large meta-analysis of 27 trials found CAB yielded a small improvement in 5-year survival (~2–3% absolute gain) over castration alone, although this benefit was modest. Thus, while CAB can provide a slight survival advantage, it also adds side effects (e.g. more fatigue, liver toxicity), so it hasn’t been definitively superior as initial therapy​. In practice, most patients were managed with ADT alone unless needed to prevent flare.

Next-generation anti-androgens and combination systemic therapy have revolutionized treatment in the last 5–7 years. Potent androgen receptor pathway inhibitors (ARPIs) like enzalutamide, apalutamide, and androgen biosynthesis inhibitors like abiraterone are now used in combination with ADT for advanced disease. Multiple phase III trials (e.g. ARCHES, ENZAMET, TITAN, LATITUDE) demonstrated that adding one of these agents to standard ADT significantly improves patient outcomes​ pmc.ncbi.nlm.nih.gov. Compared to ADT alone, ADT + ARPI leads to prolonged progression-free and overall survival in metastatic hormone-sensitive prostate cancer​. For example, adding abiraterone or enzalutamide to ADT has reduced the risk of death by ~30% or more in men with newly diagnosed metastatic disease in clinical trials​. These findings have been practice-changing – international guidelines now recommend combined therapy (ADT plus an anti-androgen) for most patients with high-volume or high-risk metastatic prostate cancer, rather than ADT alone pmc.ncbi.nlm.nih.gov. In summary, first-generation anti-androgens as monotherapy play a limited role (sometimes used in special cases for M0 disease or to block flare), whereas combination therapy using modern anti-androgens with ADT has become standard of care to maximize survival in advanced prostate cancer.

Role of 5-Alpha-Reductase Inhibitors in ADT

5-Alpha-reductase inhibitors (5-ARIs) like finasteride and dutasteride block the conversion of testosterone to the more potent dihydrotestosterone (DHT). This dramatically lowers intraprostatic DHT levels – tissue studies show >90% reductions in prostatic DHT with 5-ARI therapy​, akin to the effect of medical castration. This raised interest in adding 5-ARIs to ADT to further suppress androgens (so-called “triple androgen blockade”: LHRH agonist + anti-androgen + 5-ARI). In practice, however, clinical evidence for triple therapy is weak. Some early studies (mostly single-arm or phase II) reported promising PSA responses with triple blockade, but no randomized trial has shown a clear long-term benefit​. A review by the American Cancer Society notes that while some doctors have tried adding a 5-ARI to combined ADT, “there is very little evidence to support the use of this triple androgen blockade”​. In other words, adding a 5-ARI has not proven to improve survival or time to progression in advanced prostate cancer. As a result, 5-ARIs are not routinely included in ADT for advanced disease​ cancer.org. They are mainly used for other indications (benign prostatic hyperplasia, prophylaxis in certain settings, or in clinical trials). Current guidelines reserve 5-ARIs for chemoprevention or symptomatic benefit (e.g. shrinking the prostate) rather than as a standard component of hormonal therapy in advanced prostate cancer.

Timing of ADT Initiation: Early vs Delayed

The optimal timing of ADT in advanced prostate cancer – whether to start immediately upon diagnosis of recurrent/metastatic disease or to delay until disease progression – has been debated. Early initiation of ADT (e.g. at biochemical relapse after surgery/radiation) can slow disease progression. A 2023 systematic review of 26 studies found that early ADT in non-metastatic biochemical recurrence delays progression of prostate cancer, prolonging the time to metastasis compared to delayed therapy​ mdpi.com. However, many studies did not show a clear improvement in prostate cancer–specific survival with early ADT in this setting​. In other words, starting ADT at the first sign of rising PSA may prolong the period of disease control but hasn’t conclusively been shown to extend lifespan versus waiting until overt disease appears. Because ADT has significant side effects, clinicians often balance the risks and benefits based on a patient’s risk factors. Men with rapid PSA doubling times, high Gleason scores, or symptomatic disease are considered high-risk, and most guidelines recommend against delaying ADT in these cases​. In patients with high-risk features (or documented metastases), deferred therapy could allow preventable complications; thus, immediate ADT is advised for high-risk or symptomatic metastatic disease​. Conversely, in men with low-risk biochemical relapse (slow PSA rise, long interval from treatment), some may opt to observe until progression, to spare side effects. Overall, evidence suggests early ADT yields better disease control, but its impact on survival is unclear – so the timing is individualized. Current practice is to start ADT promptly in metastatic or high-risk recurrent prostate cancer, while carefully considering deferral in low-risk PSA-only recurrences with close monitoring​

Intermittent vs Continuous ADT

In addition to timing of initiation, the structure of ADT can be continuous or intermittent. Continuous ADT means ongoing therapy with no breaks, whereas intermittent ADT (IAD) involves cycling ON treatment for a period and then OFF treatment to allow partial hormonal recovery, repeating based on PSA or time intervals. IAD was developed to reduce cumulative side effects and improve quality of life. Importantly, multiple randomized trials have shown that intermittent therapy is not detrimental in appropriately selected patients. A large meta-analysis (including ~6,800 patients from 15 trials) reported no significant difference in overall or disease-specific survival between intermittent and continuous ADT​ cancernetwork.com. In that analysis, 8 trials contributed to overall survival and showed virtually identical outcomes (pooled HR ~1.02, no statistical difference)​. Time to castration-resistant progression was also similar between arms​. Thus, for many men, intermittent ADT achieves cancer control equivalent to continuous therapy.

Where intermittent ADT shows a clear advantage is in quality of life. Patients on IAD have treatment breaks during which testosterone levels partially recover, leading to improvements in energy, sexual function, and other domains. Trials have documented better physical and sexual well-being in men on intermittent therapy​. For example, men report improved libido and erectile function in off-treatment periods, and some studies found significantly less fatigue and better overall QoL scores with IAD​. These benefits must be weighed against the need for regular monitoring during off-cycle and the psychological aspect of stopping and re-starting therapy. In clinical practice, intermittent ADT is a common approach for men with biochemical-only recurrence or those with milder disease burden, as it can reduce long-term side effects while maintaining efficacy. However, in patients with extensive metastatic disease or very aggressive cancer, many clinicians still favor continuous ADT. There is some evidence (e.g. subgroup analyses of trials) that men with high-volume metastases might have slightly better survival with continuous therapy​. Therefore, the choice is individualized: for most non-curative cases, intermittent ADT is a valid strategy to improve QoL, with the understanding that in cases of rapidly progressive or high-burden disease, a continuous regimen may be more appropriate​. Overall, the consensus of recent studies is that intermittent therapy does not compromise survival and can be offered to reduce side effects in men who respond well to initial ADT​.

Managing ADT Side Effects

ADT induces a spectrum of side effects due to androgen deficiency. Key strategies to mitigate and manage common ADT-related toxicities include:

• Hot Flashes: Sudden vasomotor flashes affect up to 80% of men on ADT and can significantly impair quality of life pmc.ncbi.nlm.nih.gov. Avoiding triggers (heat, spicy foods, alcohol) and lifestyle measures (cooling techniques, layered clothing) are first steps. If more intervention is needed, medications can help. Low-dose progestins such as medroxyprogesterone or cyproterone acetate often reduce hot flash frequency by ~75%​. Non-hormonal options include certain antidepressants (particularly venlafaxine, an SNRI) and the neuromodulator gabapentin, which have shown efficacy in clinical trials​. These therapies can be tailored to the patient’s comorbidities. Notably, men on anti-androgen monotherapy have a much lower incidence of hot flashes (<1%) compared to those on LHRH agonists (~50%)​, and intermittent ADT is associated with significantly fewer or less intense hot flashes than continuous therapy​

• Bone Loss and Fractures: ADT causes loss of bone mineral density (roughly 4–5% loss per year in the first years) and increases fracture risk due to hypogonadism​. Preventive bone health measures are crucial. All patients should receive calcium and vitamin D supplementation (unless contraindicated), and engage in weight-bearing exercise to strengthen bone​ pmc.ncbi.nlm.nih.gov. A baseline DEXA scan to assess bone density is recommended before or soon after starting long-term ADT, with repeat DEXA every 1–2 years to monitor for osteoporosis​. If bone density is low or declines significantly (or if there’s a history of fracture), initiating a bisphosphonate (like weekly alendronate or periodic zoledronic acid) or denosumab (a RANKL inhibitor given subcutaneously every 6 months) is indicated to improve BMD​. Bisphosphonates have proven effective in preventing ADT-induced bone loss and increasing BMD​, though only denosumab has shown a significant reduction in fracture incidence in men on ADT​. Ensuring adequate bone health management can substantially mitigate the risk of osteoporotic fractures during ADT.

• Metabolic and Cardiovascular Effects: Androgen deprivation induces metabolic syndrome changes – increased fat mass, reduced muscle, insulin resistance, and unfavorable lipid profile​. Indeed, men on ADT have a 75% higher risk of developing metabolic syndrome than non-ADT controls​. These changes translate into higher long-term risks of diabetes and cardiovascular disease. To manage this, lifestyle optimization is first-line: a heart-healthy diet and regular aerobic and resistance exercise are recommended for all patients on ADT​. Exercise has been shown to counteract fat gain and improve insulin sensitivity and fitness in men on ADT​. Periodic screening of blood glucose, HbA1c, and lipid panels is advised, with treatment (e.g. metformin, statins) as needed per standard guidelines. Early research suggests metformin may help attenuate ADT-related metabolic changes; in one trial, 6 months of metformin plus lifestyle changes led to reductions in weight and blood pressure in men on ADT​. From a cardiovascular standpoint, all patients should have their cardiovascular risk factors assessed prior to ADT​. Blood pressure control, glucose control, and smoking cessation are important to lower cardiac risk. In men with pre-existing heart disease, close collaboration with a cardiologist is wise, and some clinicians opt for a GnRH antagonist for ADT in these patients given the signal of lower cardiac events (though definitive evidence is still evolving)​. Overall, proactive management of weight, diet, exercise and cardiovascular risk can significantly reduce ADT-related metabolic and cardiac complications.

• Sexual Dysfunction and Emotional Changes: The loss of testosterone causes libido loss and erectile dysfunction (ED) in the majority of men on ADT, which can be distressing. Prior to starting therapy, patients (and partners) should be counseled about these expected changes​. For ED, phosphodiesterase-5 inhibitors (like sildenafil) can be tried and may improve the mechanical ability to achieve erection​, but their benefit is often limited since sexual drive is markedly reduced. Vacuum erection devices or penile injections are alternatives for select motivated patients. Importantly, intermittent ADT can help – during off-treatment intervals, testosterone may recover enough to partially restore libido and sexual function​. This on-off cycle can allow intimate life to improve temporarily, which some couples find beneficial. Along with sexual side effects, ADT can cause emotional and cognitive effects: many men experience fatigue, mood swings, depression, or memory/concentration difficulties from low hormone levels. Regular exercise has proven helpful in combating ADT-related fatigue and even improving mood and cognitive function​. Providers should monitor for signs of depression; counseling or psychiatric referral may be needed, and medical therapy (antidepressants) can be used for clinical depression or anxiety during ADT. Engaging in social support or support groups is also valuable – knowing that these mood/cognitive effects are a recognized side effect often helps patients and their families cope better. Overall, a proactive approach addressing sexual health (with medical or mechanical aids, and considering intermittent therapy) and mental health (exercise, counseling, possibly medication) is essential to maintain quality of life on ADT.

• Gynecomastia: Enlargement of breast tissue with associated tenderness can occur particularly when non-steroidal anti-androgens (like bicalutamide) are used, due to imbalance in the testosterone–estrogen ratio. Even on LHRH agonists alone, a minority of men may develop some breast swelling. To prevent this, clinicians can employ prophylactic breast irradiation (a single low-dose radiation to the breast buds) or low-dose tamoxifen at the start of therapy, which significantly reduces the incidence of gynecomastia and mastodynia​. If gynecomastia has developed, tamoxifen (an estrogen receptor modulator) is often effective in reducing breast size and pain, and is the preferred treatment if the condition is bothersome. In severe cases unresponsive to medical therapy, surgical removal of the glandular tissue is an option. It’s worth noting that gynecomastia is more frequent with anti-androgen monotherapy (up to 50% incidence) than with LHRH-based ADT. By anticipating this side effect and taking preventive steps (radiation or tamoxifen), physicians can spare patients this discomfort in most cases​.