Editor's Note: Androgen deprivation therapy (ADT), also known as castration therapy, involves lowering male hormone levels through surgery or medication to treat prostate cancer. Recently, the 2024 Annual Meeting of the Chinese Urological Association (CUDA) was successfully held in Xi'an. Following the event, Urology Frontier invited Dr. Tao Xu, Director of Urology at Peking University People's Hospital, to share insights on the challenges and developments in prostate cancer androgen deprivation therapy.

01

Urology Frontier: What are the current challenges in prostate cancer androgen deprivation therapy?

Dr. Tao Xu: With the aging population and increased screening rates in China, the incidence of prostate cancer continues to rise. Although ADT can achieve good therapeutic results, some patients still experience disease progression. The current challenges in ADT include:

  1. Development of Resistance: Castration-Resistant Prostate Cancer (CRPC): Although ADT is initially effective for most prostate cancer patients, nearly all patients eventually progress to CRPC, where the cancer no longer responds to ADT. This is one of the most significant challenges of ADT. CRPC treatment requires more complex strategies, including novel anti-androgens, chemotherapy, and immunotherapy. Complex Resistance Mechanisms: CRPC resistance mechanisms involve various complex biological processes, including androgen receptor (AR) mutations, activation of AR signaling pathways, increased AR coactivators, and tumor cell self-protection mechanisms, making it difficult to develop new treatments targeting these mechanisms.
  2. Impact of Side Effects on Quality of Life: Osteoporosis and Fracture Risk: ADT can lead to bone loss and increase the risk of fractures. Long-term ADT significantly impacts patients’ bone health. Metabolic Syndrome: ADT may induce metabolic syndrome, including weight gain, lipid metabolism disorders, insulin resistance, and diabetes, which increase the risk of cardiovascular disease. Cardiovascular Disease: ADT is associated with an increased incidence of cardiovascular diseases, including myocardial infarction, stroke, and heart failure. Regular monitoring and management of cardiovascular risk factors are necessary for patients. Sexual Dysfunction: ADT often results in reduced libido and erectile dysfunction, severely affecting patients’ sexual health and quality of life. Mental Health Issues: ADT may cause depression, anxiety, and mood swings, requiring psychological support and appropriate interventions.
  3. Complexity in Early Diagnosis and Treatment Selection: Personalized Treatment: The condition and response of prostate cancer patients vary greatly, and selecting the appropriate treatment requires highly individualized assessments. Factors such as disease progression rate, patient age, and quality of life must be considered. Diverse Treatment Options: Various ADT drugs (LHRH agonists and antagonists) and novel anti-androgen drugs are available, each with different efficacy and side effects, requiring optimal selection based on the specific situation.
  4. Compliance and Tolerability Issues: Long-Term Treatment Compliance: Since ADT requires long-term or even lifelong treatment, patient compliance may decrease, especially when significant side effects are present. Variability in Tolerability: Different patients tolerate ADT differently; some may not tolerate the long-term side effects, necessitating adjustments or changes in treatment plans.

02

Urology Frontier: LHRH agonists and antagonists are commonly used drugs in prostate cancer androgen deprivation therapy. How should treatment choices be made?

Dr. Tao Xu: LHRH (luteinizing hormone-releasing hormone) agonists and antagonists are the main drugs for androgen deprivation therapy in prostate cancer. The choice between these drugs can be based on factors such as onset speed, disease status, side effects, and patient preferences.

LHRH Agonists:

  • Common Drugs: Leuprolide, Goserelin, Triptorelin.
  • Mechanism of Action: LHRH agonists continuously stimulate the anterior pituitary gland, ultimately leading to the downregulation of LHRH receptors and inhibiting the secretion of gonadotropins, thereby lowering testosterone levels.
  • Advantages: Extensive Experience: LHRH agonists have been used for many years, with ample clinical data supporting their efficacy and safety. Multiple Administration Routes: Options include monthly, quarterly, or biannual injections, providing convenience for patient management.
  • Disadvantages: Androgen Flare: Initial use may cause a transient increase in testosterone levels, worsening symptoms, especially in patients with bone pain or spinal cord compression. Need for Combined Anti-Androgen Therapy: To prevent androgen flare, short-term anti-androgen drugs (e.g., bicalutamide) are usually co-administered at the start of treatment.

LHRH Antagonists:

  • Common Drug: Degarelix.
  • Mechanism of Action: LHRH antagonists directly inhibit LHRH receptors in the anterior pituitary gland, quickly suppressing gonadotropin secretion and immediately lowering testosterone levels.
  • Advantages: No Androgen Flare: Rapid onset of action avoids androgen flare, making it suitable for patients requiring rapid disease control. Reduced Cardiovascular Risk: Some studies suggest that LHRH antagonists may be associated with a lower risk of cardiovascular events.
  • Disadvantages: Higher Injection Frequency: Degarelix typically requires monthly injections, which may affect patient compliance. Injection Site Reactions: Some patients may experience injection site reactions such as pain or swelling.

Factors to Consider in Treatment Choice: When choosing between LHRH agonists or antagonists, doctors should consider the following factors:

  1. Severity of the Disease: If the patient has severe pain due to spinal cord compression or bone metastasis, requiring rapid control of testosterone levels, LHRH antagonists may be more appropriate. For patients with stable disease, LHRH agonists are a common choice.
  2. Side Effect Tolerability: For patients with a history of cardiovascular disease, LHRH antagonists may be more beneficial, as they may be associated with a lower risk of cardiovascular events. For patients who cannot tolerate frequent injections, long-acting LHRH agonists may be more suitable.
  3. Patient Compliance and Quality of Life: If the patient has difficulty adhering to monthly injections, long-term injection regimens with LHRH agonists (e.g., quarterly or biannual injections) may be more manageable. Patient preferences and quality of life should be considered to ensure they can adhere to the treatment plan.
  4. Need for Combination Therapy: If LHRH agonists are chosen, consideration should be given to combining them with anti-androgen drugs at the start of treatment to prevent androgen flare.

In prostate cancer androgen deprivation therapy, both LHRH agonists and antagonists have their advantages and disadvantages. Treatment choices should be based on disease status, patient tolerability, compliance, and specific clinical needs. By conducting individualized assessments and developing the most suitable treatment plan for the patient, we can improve treatment outcomes and enhance the patient’s quality of life.

03

Urology Frontier: In recent years, several new anti-androgen drugs have been developed. How have these drugs impacted the quality of life for prostate cancer patients?

Dr. Tao Xu: The introduction of new anti-androgen drugs such as abiraterone, enzalutamide, and apalutamide has provided more treatment options for prostate cancer and improved patients’ quality of life in the following ways:

  1. Extended Survival: These new anti-androgen drugs have shown efficacy in extending progression-free survival and overall survival in multiple clinical trials. By inhibiting different pathways of the androgen receptor, these drugs can effectively delay disease progression and increase patients’ overall survival time.
  2. Disease and Symptom Control: New anti-androgen drugs can more effectively control the progression of prostate cancer, thereby alleviating symptoms: Effective disease control can reduce pain caused by bone metastasis and improve patient comfort. They can also reduce urinary difficulties and frequency symptoms caused by prostate enlargement.
  3. Reduced Side Effects: Compared to traditional chemotherapy drugs, new anti-androgen drugs have fewer side effects, and patients have better tolerability: Unlike chemotherapy, these drugs primarily target the androgen receptor pathway, resulting in lower toxicity to other systems. Some drugs (e.g., abiraterone) used in combination with corticosteroids help protect bone health and reduce the risk of fractures.
  4. Psychological and Emotional Improvement: Due to the fewer side effects and better disease control associated with new anti-androgen drugs, patients’ psychological and emotional states also improve: Stable disease and fewer side effects reduce psychological burden, resulting in decreased anxiety and depression. Additionally, patients are able to maintain better activity levels and engagement in daily life, leading to a higher quality of life.
  5. Convenient Administration: New anti-androgen drugs are typically administered orally, making them convenient for patients to use. Compared to injection therapy, oral medications are easier to take, improving patient compliance.

New anti-androgen drugs have significantly improved the quality of life for prostate cancer patients by extending survival, controlling disease and symptoms, reducing side effects, improving psychological and emotional well-being, and providing convenient administration. As physicians, it is important to consider the specific circumstances of each patient, tailoring treatment plans to achieve optimal therapeutic outcomes and quality of life improvement.

04

Urology Frontier: Looking ahead, what are the future directions in prostate cancer androgen deprivation therapy that deserve attention?

Dr. Tao Xu: The future of prostate cancer androgen deprivation therapy is broad and diverse, focusing on improving treatment outcomes, extending patient survival, enhancing quality of life, and reducing side effects. Some key areas of interest include:

  1. Precision Medicine and Personalized Treatment: Genetic Testing and Biomarkers: Through genetic testing and biomarker analysis, it is possible to predict patient responses to different treatments and choose the most effective treatment plans. Personalized Treatment: Treatment plans tailored to individual genetic characteristics and tumor molecular features can improve therapeutic efficacy.
  2. Development of Novel Drugs: New Anti-Androgen Drugs: Developing more potent and selective new anti-androgen drugs to overcome resistance issues with existing drugs. Dual-Target Drugs: Developing drugs that target both the androgen receptor and other key pathways to enhance therapeutic outcomes.
  3. Combination Therapies: Combination of Anti-Androgen Drugs and Chemotherapy: Studies have shown that combining anti-androgen drugs with chemotherapy can significantly improve treatment outcomes. Anti-Androgen Drugs and Immunotherapy: Exploring the potential of combining anti-androgen drugs with immunotherapy (e.g., PD-1/PD-L1 inhibitors) to stimulate the patient’s immune system to fight cancer cells. Combination of Radiation Therapy and ADT: For locally advanced prostate cancer patients, combining radiation therapy with ADT can improve treatment outcomes. Combination of Minimally Invasive Surgery and Drug Therapy: In certain cases, combining minimally invasive surgery with drug therapy can better control the tumor.
  4. Application of Biomarkers: Circulating Tumor DNA (ctDNA): Monitoring molecular changes in the tumor in real-time through blood ctDNA testing can evaluate treatment effectiveness. Markers Beyond PSA: Developing more sensitive and specific markers to evaluate treatment response and prognosis earlier and more accurately.
  5. Side Effect Management: Bone Protection Therapy: Combining bone-protective agents (e.g., bisphosphonates and RANKL inhibitors) to prevent and treat osteoporosis and fractures caused by ADT. Cardiovascular Protection Measures: Developing and applying effective cardiovascular protection measures, such as using cardiovascular protective drugs and regularly monitoring and managing cardiovascular risk factors, to address cardiovascular risks associated with ADT. Nutritional and Exercise Guidance: Providing personalized nutritional and exercise recommendations to mitigate the side effects of ADT and improve patient quality of life. Psychological Support: Offering psychological counseling and support groups to help patients cope with potential psychological and emotional issues during treatment.
  6. Immunotherapy: CAR-T Cell Therapy: Researching CAR-T cell therapy for prostate cancer, using gene editing to enable the patient’s T cells to recognize and kill prostate cancer cells. Vaccine Therapy: Developing therapeutic vaccines targeting prostate cancer-specific antigens to stimulate the patient’s immune system to attack cancer cells.
  7. New Technologies and Methods: Data Analysis and Predictive Models: Utilizing artificial intelligence and big data technology to analyze large amounts of patient data, predict treatment response and prognosis, and optimize treatment decisions. Image Analysis: Improving early diagnosis and staging accuracy of prostate cancer through AI-assisted medical image analysis. Targeted Drug Delivery: Using nanotechnology to develop targeted drug delivery systems that precisely deliver drugs to cancer cells, enhancing efficacy and reducing side effects.

Conclusion: The future development directions for prostate cancer androgen deprivation therapy include precision medicine, personalized treatment, novel drug development, combination therapies, biomarker applications, side effect management, immunotherapy, and the application of new technologies and methods. Research and application in these areas are expected to significantly improve the survival rates and quality of life for prostate cancer patients, ushering in a new era of prostate cancer treatment. As physicians, we must stay abreast of the latest advancements in these fields and integrate them into clinical practice to provide patients with the most advanced and effective treatment plans.

Dr. Tao Xu

  • Chief Physician, Professor (Second Level), Doctoral Supervisor
  • Director of the Urology Department, Peking University People’s Hospital
  • Deputy Director, Peking University Institute of Lithotripsy
  • Deputy Director, Department of Urology, Peking University Health Science Center
  • Vice Chair, Urology Branch, Beijing Medical Association, Chair of the Basic and Translational Research Group
  • Member, Urology Branch, Chinese Medical Association, Deputy Chair of the Laser Group
  • Vice President, Urology Branch, Chinese Equipment Association
  • Standing Committee Member, Urology Specialist Branch, Chinese Medical Doctor Association, Secretary General of the Oncology Group
  • Member, Urological and Male Genital Tumor Professional Committee, Chinese Anti-Cancer Association
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Last updated on 2024.08.22