Role of LHRH Analogues in Carcinoma Prostate

1. Role of LHRH Analogues in Carcinoma Prostate Dr Harprit Singh HOD, Urology Mercy Hospital, Jamshedpur

2. Introduction • Androgens stimulate prostate cancer cells to grow. • Main androgens in the body are testosterone and dihydrotestosterone (DHT). • Most of the androgens are made by the testicles, but the adrenal glands also make a small amount. • Hormone therapy is also called androgen deprivation therapy (ADT) or androgen suppression therapy.

3. Aim • Goal is to reduce levels of male hormones, called androgens, in the body, or to stop them from affecting prostate cancer cells. • But hormone therapy alone does not cure prostate cancer.

4. Indications of Hormone Therapy • Cancer has spread too far to be cured by surgery or radiation, • Cancer remains or comes back after treatment with surgery or radiation therapy • Along with radiation therapy as initial treatment (high Gleason score, high PSA level, and/or locally advanced) • Before radiation to try to shrink the cancer to make treatment more effective

5. Treatment to Lower Androgen Orchiectomy (Surgical Castration) • Simplest, • Outpatient procedure, • Least expensive, • Permanent • Acceptance is an issue at times • Testicular implants can be offered

6. LHRH Analogues LHRH agonists (Chemical castration or Medical castration) • Luteinizing hormone-releasing hormone (LHRH) agonists (also called LHRH analogs or GnRH agonists) are drugs that lower the amount of testosterone made by the testicles. • More frequent visits to clinic • Costs more • Injected either subcutaneously, intramuscularly or as implants under the skin • Monthly, 3 or 6 months depot • Shrink the testis or too small to feel over a period of time

7. Contd… • Leuprolide (Lupride, Eligard) • Goserelin (Zoladex) • Triptorelin (Pamorelin) • Flare- LHRH agonists are first given, testosterone levels go up briefly before falling to very low levels. - Men with bony mets may have bone pain. - Patient with spinal mets, even a short-term increase in tumor growth, could press on the spinal cord and cause pain or paralysis. • Flare can be avoided by giving drugs called anti-androgens for a few weeks when starting treatment with LHRH agonists. Available in India

8. LHRH antagonist • Degarelix (Firmagon) is an LHRH antagonist. • They bind immediately and competitively to LHRH receptors • Lowers, LH, FSH & testosterone levels more quickly • No tumor flare • Monthly injection under the skin • Increased LFT • Allergic reaction due to release of histamine

9. Anti-androgens • Androgens have to bind to a protein in the prostate cell called an androgen receptor to work. • Anti-androgens are drugs that bind to these receptors so the androgens can’t. • Drugs available are • Flutamide • Bicalutamide • Nilutamide • They are taken daily .

10. Indications • Adjunct to Castration- anti-androgen may be added to treatment if orchiectomy or an LHRH agonist is no longer working by itself. • Combined androgen blockade (CAB)as first line hormone treatment- but now controversial • Prevent a tumor flare for few weeks • Anti-androgen withdrawal effect - anti-androgen is no longer working, simply stopping the anti-androgen can cause the cancer to stop growing for a short time

11. Contd… • Enzalutamide (Xtandi) and apalutamide (Erleada) are newer types of anti-androgens. • Normally when androgens bind to their receptor, the receptor sends a signal to the cell’s control center, telling it to grow and divide. • These drugs block this signal. They are taken every day

12. Contd… • Castrate-Resistant Prostate Cancer, Enzalutamide is typically used for metastatic cancer while • Apalutamide is typically used for non-metastatic cancer.

13. Other Androgen-Suppressing Drugs • Estrogens (female hormones) • Ketoconazole

14. Side effects of hormone therapy • Reduced or absent sexual desire • Erectile dysfunction (impotence) • Shrinkage of testicles and penis • Hot flashes, which may get better or go away with time • Breast tenderness and growth of breast tissue • Osteoporosis (bone thinning), which can lead to broken bones • Anemia (low red blood cell counts) • Decreased mental sharpness • Loss of muscle mass • Weight gain • Fatigue • Increased cholesterol levels • Depression

15. Side effects of Anti-androgens • Anti-androgens have similar side effects. The major difference from LHRH analogues is that anti-androgens may have fewer sexual side effects. • Enzalutamide and apalutamide can cause diarrhea, fatigue, and worsening of hot flashes and like dizziness, can have more falls • Abiraterone can cause joint or muscle pain, high blood pressure, fluid buildup in the body, hot flashes, upset stomach, and diarrhea.

16. CYP17 inhibitor • LHRH agonists and antagonists can stop the androgens made by testicles. • But other cells in the body, including prostate cancer cells themselves, can still make small amounts, which can fuel cancer growth. • Abiraterone blocks an enzyme called CYP17, which helps stop these cells from making androgens • Abiraterone has no effect on testicular androgens

17. Contd… • Men who haven’t had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. • Abiraterone also lowers the prednisone, so this needs to be substituted during treatment • High risk(cancer with a high Gleason score, spread to several spots in the bones, or spread to other organs) • Castrate-resistant(cancer that is still growing despite low testosterone levels from an LHRH agonist, LHRH antagonist, or orchiectomy)

18. Current Issues in hormonal Treatment • Early stage prostate cancer – who are not ready for surgery or radiation • Early Vs Delayed Treatment • Rising PSA after surgery or radiation • Men with advance CA who are asymptomatic

19. Contd…. • Intermittent versus Continuous hormone therapy • hormone therapy become resistant to this treatment over a period of months or years • treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again • break from side effects like decreased energy, sexual problems, and hot flashes. • Better quality of life

20. Contd… • Combined androgen blockade (CAB): both androgen deprivation (orchiectomy or an LHRH agonist or antagonist) plus an anti-androgen • Triple androgen blockade (TAB): a 5-alpha reductase inhibitor – either finasteride or dutasteride– to the combined androgen blockade. – little evidence

21. Castrate-resistant Vs Hormone-refractory • These terms are used interchangeably to describe prostate cancers that are no longer responding to hormones, although there is a difference between the two.

22. Contd… • Castrate-resistant means the cancer is still growing even when the testosterone levels are as low as what would be expected if the testicles were removed. • Specifically meant to refer to these cancers, some of which might still be helped by other forms of hormone therapy, such as the drugs abiraterone, enzalutamide, and apalutamide.

23. Contd.. • Hormone-refractory refers to prostate cancer that is no longer helped by any type of hormone therapy, including the newer medicines.

24. Take Home Message • LHRH agonists should be combined with antiandrogens to prevent flare • LHRH Antagonist has rapid decrease in LH and FSH and testosterone without flare • No need for combination therapy with antagonist • Consensus on intermittent therapy is still not there • None of this therapy alters the long term survival • EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer, EUROPEAN UROLOGY 71 (2017) 630–642

28. thank you