The question has been asked here before. Perhaps someone will provide the link to the thread.
The current issue of Prostatepedia includes an article on the subject [1]. Seems worthwhile to post it here, since many men on (classic) ADT + Abiraterone may be unaware of the SPARE trial results presented at ASCO last year [2].
"Since the approval of the second generation LHRH Therapies like Abiraterone acetate (Zytiga) plus prednisone (AA+P), many men we talk with at Cancer ABCs have been asking us if it is vital to continue taking first-line ADT (hormone therapy).
"ADT, which causes castration, or the removal of androgens such as testosterone from the body, comes with many significant adverse side effects. These side effects include loss of libido, loss of bone mass, causing an increased risk of fractures, hot flashes, cardiovascular complications, metabolic complications like diabetes, etc. Given the host of ADT's potential complications, can stopping ADT improve the quality of life while not compromising the prostate cancer treatment?
"In an abstract, 5046, presented at the 2019 Virtual ASCO Meeting, this question was asked. The abstract provided us with a summation from the SPARE-trial (NCT02077634); CH Ohlmann, C Ruessel, R Zillman, et al. asked what would happen if men with metastatic castrate resistant prostate cancer who were chemotherapy naive and who were taking Zytiga stopped first line ADT.
"The SPARE-trial was an exploratory phase II study, including 67 men. In the trial, the subject men were randomized to receive continued ADT plus Zytiga and prednisone or Zytiga plus prednisone alone(without ADT) to determine the value of continuing ADT.
"The researchers found that in all men who received Zytiga plus prednisone and ADT, their median testosterone levels remained below castrate levels throughout treatment.
"In 18% of the men who only received Zytiga and prednisone (no ADT), their testosterone levels increased above castrate levels 28 days after treatment cessation.
"They also found that the median treatment duration was shorter in the men receiving Zytiga plus prednisone and ADT.
"The researchers concluded that ADT may not be necessary for men receiving Zytiga and prednisone; however, some men may experience a rapid increase of serum testosterone levels, warranting close monitoring and adding back ADT.
"This research is not conclusive and only evaluated the possibility of halting ADT while taking Zytiga and prednisone. It did not evaluate stopping ADT with any other second-generation hormone manipulations like Xtandi or Darolutamide.
"CAUTION
"Under no circumstances should you stop your primary ADT treatment without a careful conversation and your medical oncologist's agreement. If you and your oncologist decide to stop ADT, you and your doctor must develop a cautious plan to AGGRESSIVELY AND CONTINUOUSLY monitor your serum testosterone levels."
***
You are probably wondering about the significance of:
"They also found that the median treatment duration was shorter in the men receiving Zytiga plus prednisone and ADT."
Median treatment duration was 266 days [ADT + Abi] versus 420 days [Abi].
Time to PSA progression was 288 days [ADT + Abi] versus 336 days [Abi].
I'm also wondering about this: "some men may experience a rapid increase of serum testosterone levels, warranting close monitoring and adding back ADT."
I'm confused. Are they suggesting T recovery is dangerous in and of itself, even without rising PSA or other signs of cancer progression?
"ADT is considered to be effective when serum testosterone has declined to the recommended levels of 50 ng/dL, according to the 2012 National Comprehensive Cancer Network guidelines" (from my response to 6357axbz)
So doctors might be disinclined to test for "rising PSA or other signs of cancer progression".
As discussed elsewhere, DHT (dihydrotestosterone) is the ultimate target of hormonal therapy. Could be prudent to take Avodart (IMO).
Yes, my MO suggested finasteride along with my bicalutamide. I always thought that Dr. Bob's idea of "Proscar maintenance" made sense, so long as you accounted for the additional "unnatural" reduction in measured PSA levels.
Zytiga also works by lowering testosterone...so in reality zytiga is Androgen deprivation therapy. Because it does deprive a man of androgens albeit from all three sources of androgens. i.e. testicles, adrenals and prostate cancer cells themselves.
My opinion is that the same principles apply with zytiga monotherapy which apply on leuprolide because the net result in both is androgen deprivation.
And just like with plain Leuprolide where some men's T goes below 20 and other men's testosterone stays above 20, 50 or even higher...I think the same might happen with Zytiga
monotherapy. There is a lot of variation in individual response to every treatments..so it is quite possible that Zytiga monotherapy might be just enough in some....just like many people do fine with bicalutamide monotherapy alone.
Has anyone here trended towards diabetes or developed diabetes due to ADT? My A1C edged up to 6. First time in my life it moved out of the guidelines. I’m not overweight at all.
The following is from a meta-analysis on the subject [1]:
"The present study carried out a meta‐analysis involving eight observational studies with a total of 157,588 PCa patients, and showed that ADT was associated with diabetes. The direct evidence was proved by Keating et al.10, showing a significantly increased risk of diabetes over a median follow‐up period of 4.55 years in GnRH users with PCa (HR 1.44, P < 0.001). One cross‐sectional study24 also found that men on ADT had a higher prevalence of abdominal hyperglycemia.
"ADT is considered to be effective when serum testosterone has declined to the recommended levels of 50 ng/dL, according to the 2012 National Comprehensive Cancer Network guidelines29. However, low serum testosterone levels might decrease lean body mass and increase fat mass30, and might also reduce insulin sensitivity31, resulting in insulin resistance. Furthermore, obesity and insulin resistance are strongly associated with type 2 diabetes mellitus32. Taken together, all of those aforementioned supported our finding that ADT is a risk factor for diabetes.
"Among included publications, four studies7, 10, 26, 27 were large‐scale cohort studies, and all the others23, 24, 25, 28 were cross‐sectional studies. No trials met the inclusion criteria of our meta‐analysis. To ensure the quality of the included studies, we carried out a sensitivity analysis only including cohort studies. When cross‐sectional studies were ruled out of consideration, RRs were obtained, and the analysis result was similar to the overall analysis and achieved the reduction of heterogeneity.
"Because varied types of ADT were reported in two eligible studies10, 26, bias might exist in the results of overall analyses. In order to reduce this heterogeneity, subgroup analyses stratified by ADT type were carried out. A significantly increased risk of diabetes was associated with GnRH, GnRH plus AA and orchiectomy, but not with AA monotherapy. Treatment with antiandrogen monotherapy is not approved for PCa in the USA, so few men likely received such therapy.22 GnRH agonist could be responsible for diabetes toxicity through indirect mechanism, in which hypogonadism plays a critical role in the onset of metabolic syndrome33. The direct evidence proved by Keating et al.26, evaluating the relationship between GnRH agonist and diabetes events over a median follow‐up period of 2.6 years in men with PCa, was in accordance with our findings that GnRH agonist could significantly increase the risk of diabetes morbidity (adjusted HR 1.48, 95% CI 1.31–1.67). However, the present meta‐analysis had limitations that should be acknowledged. First, two or more types of ADT groups from two articles10, 26 were respectively compared with the same control group. Random effects meta‐analysis was used to combine these data together for compositing overall RRs. Second, all eligible publications were retrospective observational studies, which could introduce recall limitation so that the integrity of the records weakened the reliability of the results. However, as one adverse effect of ADT, diabetes is not the main end‐point randomized controlled trials always focus on, and the strict inclusion in randomized controlled trials might lead to the limitations of external validity as a result34. For the purpose of investigating adverse drug reactions, it is more credible to carry out a large‐scale observational study with long duration of follow up, high quality of design and implementation. Third, there was not an adequate number of studies available for the subgroup analysis of short duration of ADT. We tried to add the short duration to our subgroup analysis only for comparison with long duration of ADT. As to the different types of ADT, there was the same problem that only one study was available for AA and GnRH plus AA. We are aware of this limitation that the analysis result of AA and GnRH plus AA might be not credible; these results were only for comparison with other therapies. Furthermore, the basic characteristics of patients (e.g., age, the stage of PCa, comorbidities) with or without ADT might be different, and these could affect the incidence of diabetes. However, the HRs directly given in all of our included cohort studies7, 10, 26, 27 were already adjusted for the baseline characteristics of patients. Therefore, the influence of mixing basic characteristics of populations on our meta‐analysis would be minimized. Finally, the present study only included articles with binary variables reporting diabetes morbidity as the end‐point, but studies with continuous variables (e.g., fasting blood glucose or fasting serum insulin) were ruled out. However, this potential bias is likely to have been minimal, because the result of this meta‐analysis was similar to the studies35, 36 only reporting continuous variables that ADT users had a significantly higher glucose level compared with controls.
"In conclusion, this meta‐analysis proves that ADT is associated with diabetes. Subgroup analyses show that GnRH, GnRH plus AA and orchidectomy can significantly increase the risk of diabetes. Additionally, diabetes is significantly related to long duration of ADT (≤6 months), and is slightly associated with short duration (>6 months). The present findings might help clinicians be conscious of the potential risks of ADT and ensure medical safety. Additionally, randomized controlled trials are required to further investigate the relationship between ADT and diabetes."
It says, "However, low serum testosterone levels might decrease lean body mass and increase fat mass30, and might also reduce insulin sensitivity31, resulting in insulin resistance."
Is there a good source on which ADT side effects are a result directly of low T itself, and which are a derivative result actually associated with lower estrogen levels (that RESULT indirectly from low T)?
I am just wondering if it is as simple "loss of muscle come from no T" and "decreased insulin sensitivity comes from no E" and so forth.
My fasting blood sugar went up to 150 after being on and off of Casodex monotherapy for 15 months. I been on a Casodex vacation for a month and my fasting blood sugar now runs about 115-125. Last A1C was 6.5.
Thanks Patrick. I always wondered about this. Some MOs will not discontinue ADT because the clinical trials were done with ADT. I already had a discussion about this situation with one of the MOs I consulted at UCSF. After a shot of Lupron my testis went to sleep and my testosterone is unmeasurable (free Lupron situation), and he wanted me to start Lupron.
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High Gleason low PSA - quit ADT? 
Adding Zytiga Post-Chemo - necessary?
