ADT Optimizing its Role in Advanced P Ca: Challenges beyond Guidelines

Dear All,

I am providing an article published on March 4th by Neal Shore and his panel of over 14 members who have looked into ‘Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines’.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/pros.23967 (PDF available)

Practicing Urologists have used ADT in various forms for ~80 years from localized P ca to its most advanced stage. Initially it was Bil. Orchidectomy followed by Oestrogens prior to ADT taking over in 1980’s. Even today there is no consensus as regards the superiority of CAB over Bil. Orchidectomy even though volumes have been written on this subject. Since the turn of the century, especially since 2010, There have been several molecules introduced into the realms of treatment claiming longer overall survival. Today we talk about Abiraterone, Enzalutamide as monotherapy and even in combination. Drugs like Apalutamide/Darolutamide are being touted as the drugs for prolonging survival. Chemo hormonal therapies are touted as specific under special circumstances. So many more, including Checkpoint inhibitors, are on the anvil and time will inform us regarding their utility.

However, even today, Hormonal therapies rule the roost as regards management of Advanced P Ca.

This panel consensus on optimising the role of ADT in advanced P ca is a must read and understanding. They opine that ‘In the medical literature, there is a lack of level 1 evidence to make conclusive statements about ADT use in all settings’.

I am sure this consensus will inform us regarding the usefulness and limitations of use of ADT in todays context.

With warm Regards,

Venu

 

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Comments(1)

  • Venugopal P
    Venugopal P
    10 Jun 2020 10:09:38 AM

    Relugolix – Oral GNRH Antagonist for P Ca

    Dear All,

    The post above on March 20th has been received with scant attention of our members.  Anything new arrives, the old is given a cold shoulder and put in cold storage as is the norm of human beings. Suddenly the old (molecules in this case) assumes considerable adverse effects making one wonder what a folly it was in using them. But is the new gold and it is likely that they too can suffer the same as old in near future. Another aspect that defies logic is that any molecules that are cheaper is considered inferior to one that is costly and this is a problem we face in India as many of our patients are financially strapped and for them such costly drugs will surely drain the purses. Do we take these considerations when we consider the treatments that are being offered? Add to this the various pharma manufacturing the said cheaper drug stops manufacturing as it for them they are non profitable.

    Huggins and Hodges informed us of P Ca being Hormone sensitive way back in the year I was born ie 1940. Surgical castration was the option recommended and in 1980, Scully introduced LHRH agonists for use for P Ca and soon Medical Castration replaced Surgical Castration (the former being more costly) on the premise that Surgical Castration was permanent and induced psychological problems due to loss of testes. In 2009, Trials began on the use of Degarelix (LHRH Antagonist) and soon was shown to be probably superior to the usually used LHRH Agonists (and being costlier as well and hence better). Antagonists were found to have no initial Testosterone Surge as seen with Agonists and hot flashes as seen with Agonists were fewer. But it has to be given as monthly injection. The cost of Degarelix is ₹35,000/-.  By 2010, Abiraterone followed by Enzalutamide arrived on the scene to treat advanced P Ca with enhancing costs

    The cost of Abiraterone 250mg is ₹16,000 for a bottle of 120 tablets (the dose required is 1000mg a day). Soon after Enzalutamide emerged which costs ₹8,71,973 for a 30 day’s supply. Though several studies have shown its effectiveness, a fact that has emerged is that both can develop resistance soon and studies of Emmanuel Antonorakis suggest that AR V7 estimation in circulating cancer cells should be performed prior to initiation of these drugs so as to assess their effectiveness. The two new introductions, claiming superiority over Enzalutamide are Apalutamide and Darolutamide. They are more or less similar in pricing at Apalutamide 8,80,991 and Darolutamide 8,71,973 for 30 day supply.

    Now study has changed to Oral LHRH Antagonist (Relugolix) as an effective alternative to be used as an ADH. This is not a new drug in the market and is being used as an alternative for treatment of Fibroid Uterus and the like. For these uses, a lower dose of the drug suffices but for P Ca, the dose of the drug will have to be escalated.

    Relugolix is a novel oral non-peptide GnRH receptor antagonistx22Miwa, K., Hitaka, T., Imada, T., Sasaki, S., Yoshimatsu, M., Kusaka, M. et al. Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl )-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem. 2011; 54: 4998–5012

    PubMed | Google ScholarSee all References(22)
    . Relugolix competitively inhibits GnRH receptors on the anterior lobe of the pituitary, thereby directly inhibiting secretion of LH and FSH
    .

    Neal Shore who led the HERO Phase III Trial mentioned that Relugolix has the ‘potential to become a new standard for ADT and advanced prostate cancer’. The phase III study was conducted over 900 patients demonstrated that castration at 48 weeks was maintained in 96.7% of men vs 88.8% for patients using Leuprolide. (Excerpts from his presentation at ASCO 2020 is being provided)

    It also cut the risk of major adverse cardiovascular events by 54% as compared to Leuprolide. Patients were given 360mg as the initial loading dose and were given 120mg daily then onwards. On day 15 of use of Relugolix, 98.7% showed Testosterone suppression to <20ng/dL. In addition the PSA response noted at 15 days was 79.4% with Relugolix and 19.8% with Leuprolide. Among the side effects, Hot flashes are said to be lower with Relugolix. Diarrhoea was reported in a higher percentage of patients in the Relugolix group (12.2%) than in the Leuprolide group (6.8%).

    Relugolix, 100 tablets of 40mg, cost 1,07,538.

    These drugs however effective they could be will be out of reach of many Indians and this is a point that will have to be given importance when suggesting these drugs. There is a saying ‘cut the sleeves based on material available’ is apt in Indian Circumstances. The treatments we offer should be affordable for the majority and not for the select few.

    I know that I have placed my head on the chopping block when I utter such a statement but I am willing to be axed.

    With warm Regards,

    Venu

     

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