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