Importance of bone meds for men with CRPC on ADT

Well, that is interesting as it was shown before that Zometa did not prevent new bone tumor growth. This study in mice has demonstrated it does. How do we reconcile?

Tall Allen said...
SpecialLady-

Two important aspects here are (1) the mice had only the castrate-resistant variety of PC and (2) the mice were castrated (ADT/chemical castration would probably amount to the same thing.) It is not that Zometa prevented new bone tumors, it is that castration (or ADT) increased the rate of bone tumor formation. In fact, Zometa did not prevent new bone tumor growth at all when ADT/castration was not present.

- Allen

Hi Allen, I did not read the whole study, just this preprint, but what they are saying is indeed what you write: 1. Castration increased the rate of bone tumor formation. But they are also saying that 2. Zometa prevented new bone tumors in castrated animals.

Their conclusion "first biological evidence supporting administration of ZOL to prostate cancer patients at the time of androgen ablation to prevent subsequent relapse in bone." is pretty much opposite of what other studies are saying, like this one Zoledronic Acid Fails to Halt Metastasis in Prostate Cancer where we can assume, most subjects receiving Zometa are also on Lupron. Now, that population of patients may be mixed androgen-sensitive and insensitive. Do you think if they singled out androgen-insensitive patients, they would see a difference in Zometa preventing new bone tumors?

In addition, it would have been a better designed study if there were additional two groups of mice that were innoculated with androgen-sensitive variety of PC.

Post Edited (SpecialLady) : 7/27/2014 2:47:30 AM (GMT-6)

Allen,

So do you suppose that Zometa would be given at the first hint of any PSA rise on ADT or while the cancer is androgen sensitive realizing that in time it would become resistant?

Paul

I went onto Xgeva as soon as I turned 65 and Medicare covered it, but supposedly the practice, and I agree with Tall Allen it makes no sense, is to wait for the first so called skeletal event before starting Xgeva or Zometa.

Seems to me horse is already out of the barn at that point.

Now that I no longer am deemed to have bony mets, switched from Xgeva monthly to Prolia every 6 months, since Lupron is also tough on bones even when one does not have bony mets.

Topic on this thread however was CRPC (Not sure if intention was mCRPC or just CRPC), and I am either just starting to become so with an increase from 0.10 to 0.23 before dropping again after starting Zytiga to 0.07 and then to <0.04.

or at least trying on paper to appear so in order to qualify for Provenge by deferring the Zytiga, but have been on Lupron since 3-28-13 and Xgeva from 8-1-13, next PSA on July 31 will hopefully be >=0.04 to show the first of 2 increases from <0.04.

LupronJim

Allen,

This subject is of much interest to me and the study is very interesting. I'd appreciate your thoughts on the following...

Just about the time I was diagnosed over a year and ½ ago my oncologist wanted to start me on Zometa shortly after starting ADT. I had a dental issue that needed tending, so immediate starting was not possible. I also saw this article advancedprostatecancer.net/?p=3724, which caused me concern, and to seriously question the benefit of starting Zometa while still castrate sensitive.

To confuse me even more, I went to Zometa's website www.us.zometa.com/index.jsp?usertrack.filter_applied=true&NovaId=2935376979265776196 and for Prostate Cancer, it clearly showed being prescribed “*Following at least one course of failed hormonal therapy”.

So what existing clinical data was there that had so many doctors prescribing it while patients were castrate sensitive? I think even the NCCN guidelines suggest it be given while castrate sensitive. I figured there must have been some supporting evidence via a study and/or trial, but I never found one.

Would not they have seen a similar effect on patients in the trial that was ended early, as was seen in the mice study? Or was the design of the trial simply measuring SRE's and overall survival, therefore missing an important benefit?

More recently I saw a Myers video on the subject askdrmyers.wordpress.com/ scroll to the Bone Loss During ADT video, which suggests other options for some patients. I will be asking him for a recommendation based upon my current medical status. During my last visit at NIH the nurse suggested I talk with my onco about starting either Xgeva or Zometa and I know I need to do something. If Myers suggests his therapy over Zometa or Xgeva, it will be interesting to see how that is received by the other docs.

Any thoughts on Myers video / approach?

While the CALGB 90202 trial showed that Zometa may not be a benefit in slowing down skeletal related events (SREs) in men taking ADT while they were still hormone sensitive, I'm not at all sure that the same can be said for Xgeva or Forteo. I know Dr Scholz routinely prescribes Prolia (Xgeva lite) for all men on ADT. In an RCT on Xgeva for men taking ADT, it increased bone mineral density and the effect was even greater among men who'd just started on ADT within the last 6 months. The relative incidence (to placebo) of new fractures declined the longer they stayed on it.

To add to the confusion, when taken at the beginning of hormone therapy by men with diagnosed mets, Zometa+ADT delayed PC progression compared to ADT alone by nearly a year, and delayed SREs, and the difference was especially significant in men with GS 8-10.

Efficacy of combined androgen blockade with zoledronic acid treatment in prostate cancer with bone metastasis: The Zoledronic Acid/Androgen Blockade Trial on Prostate Cancer (Zabton-PC) study.

In another study, high-risk men who had biochemically failed RP or RT were started on ADT. If they were given bisphosphonates when starting ADT, it delayed the time to the first appearance of a met nine-fold. Perhaps this case is similar to the above, except that this group had micromets that were not yet imageable.

Adjuvant Effect of IV Clodronate on the Delay of Bone Metastasis in High-Risk Prostate Cancer Patients: A Prospective Study

I think transdermal estrogen, selective estrogen receptor modulators (SERMs) like toremiphene, Forteo, and Xgeva may all be effective in preventing bone loss and fractures while on ADT while the cancer is still hormone sensitive. Zometa and other bisphosphonates seem to work only after CRPC sets in, or when there are mets already present, or after treatment failure.

- Allen

Post Edited (Tall Allen) : 7/28/2014 11:30:47 PM (GMT-6)

I came across another one today that seems to confirm what the above two studies are telling us, but seems to contradict the finding of the CALGB 90202 study. They found that Zometa, given at the initiation of ADT in men with HSPC and bone mets, delays the time to PSA failure and first SRE. The only differences that I can see are that (1) this study included Casodex as well, and (2) this looked at time to progression rather than and overall survival (but they both looked at time to first SRE), and (3) it was done in Japan.

In fact, there are a few Japanese RCTs that show a benefit to Zometa when started while it is hormone sensitive with bone mets (mHSPC). Racial differences?

Zoledronic Acid Improves Clinical Outcomes in Patients with Bone Metastatic Hormone-naïve Prostate Cancer in a Multicenter Clinical Trial.
charts showing benefit in PSA failure and time to first SRE

This one notes that overall survival was extended too:Possible anti-tumor activity of initial treatment with zoledronic acid with hormonal therapy for bone-metastatic prostate cancer in multicenter clinical trial.

This one allows you to read the full text (click at right):
Additive effect of zoledronic acid on serum prostate-specific antigen changes for hormone-sensitive prostate cancer patients with bone metastasis treated by combined androgen blockade.


This is the one from above:
Efficacy of combined androgen blockade with zoledronic acid treatment in prostate cancer with bone metastasis: The Zoledronic Acid/Androgen Blockade Trial on Prostate Cancer (Zabton-PC) study.

And this is the contradictory US RCT:
Randomized Controlled Trial of Early Zoledronic Acid in Men With Castration-Sensitive Prostate Cancer and Bone Metastases: Results of CALGB 90202 (Alliance)

Any Sherlocks who can resolve the discrepancy? Are Japanese bones that different from US bones?

- Allen