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Post by Allen on Aug 1, 2014 18:44:28 GMT -8
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Post by Tony Crispino on Aug 14, 2014 15:16:32 GMT -8
Allen, Men with bone mets are frequently started right away with ZA. But keep in mind the #1 related terrible SE of Zometa ~ Necrosis of the jawbone. The longer you are on it themore likely you encounter these issues: Zometa SE'sWe can try Nick on this... |
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Post by Tony Crispino on Aug 14, 2014 19:48:35 GMT -8
Allen,
OK, I read these links and documents. You do realize that the Japanese trials combined had less than 110 patients treat with CAB-Z.The Alliance trial had 658 that were treated with both CAB and ZA. I do not see a huge difference in the Japanese trials from the Alliance trial. In addition the Alliance trial accrued 645 versus 265 in the Japanese trials (Hiroji et al was not a trial) What the Japanese called significant was the 11.3 months before progression in the arms however overall survival in both the Japanese and Alliance trials was ~ insignificant
Hiroji et al accrued 49 patients and reported in 4/2012 was not a trial but a comparison. Level III data Too small and not RCT Not really meaningful
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Okegawa et al
100 with ZA, 105 without ZA. PSA failure was 40 and 48 respectively. Interestingly, the study states 40% versus 48% but 48 of 105 is actually 45% not 48%.
Ueno only had 60 accrued only 29 with ZA. Observed a significant difference especially in men with extensive mets. But how many men has significant difference is a cohort of 29 en? That is a very small cohort.
"The first end point was a period to PSA relapse, and the secondary end point was SREs rate."
"Though careful observation is essential, since the long-term use of ZA may increase the incidence of adverse effects, CAB-ZA treatment may be recommended for the treatment of PCa patients with bone metastasis."
Alliance trial Smith Et Al
This trial was terminated prior to full enrollment. Goal was 680 accrued and 645 actual
There were 299 SRE's with the median SRE of 31.9 months in the ZA arm and 29.8 in the control are. Basically 46% SRE's overall
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Lastly: The CHAARTED trial question you ask:
Should Zometa (or Xgeva) as well as docetaxel (as per the CHAARTED study) be started along with ADT as soon as possible when PC with bone mets is diagnosed?.
> Well first remember that when mets were low volume the benefits of the early docetaxel were not conclusive.
> When extensive mets occurred (4 or more or visceral) this is a no brainer. Yes on the Chemo. Probably not good to lead with ZA but rather wait until they were chemo refractory.
So Japan trials ~ too small. Alliance trial conclusive and terminated early as the question was answered and there was no improvement in SRE's while the patients were effectively being treated with CAB
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twolf
Junior Member
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Post by twolf on Aug 18, 2014 17:11:24 GMT -8
You are not mentioning Prolia. Should this not be the first bone density drug to be considered when going on ADT?
Essentially the same drug as Xgeva, but at a much lower dosage.
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Post by Tony Crispino on Aug 18, 2014 17:47:56 GMT -8
Hi TWolf, and welcome.
You are very correct in that suggestion. I was prescribed Fosamax as a prophylactic drug to prevent osteoporosis. So there are variations that are possible such as:
Zoledronic acid (Reclast, Zometa)
Teriparatide (Forteo)
Alendronic acid (Fosamax)
Ibandronic acid (Boniva)
Raloxifene (Evista)
I have seen variations from those I have met that were on the same therapies I was on. I believe that both Forteo and Evista are estrogenic so I can see why maybe not for the guys. But all of the acids and Prolia/Xgeva are absolutely suitable. My understanding is that the Fosamax approach is the least expensive and is available off patent. It is probably the most common anti-SRE drug out there for early HT cases.
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twolf
Junior Member
Posts: 16
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Post by twolf on Aug 18, 2014 19:03:09 GMT -8
Tony, you make it sound like Fosomax and Prolia are the same, but they are quite different.
If you read up on Forteo, it is not recommended for patients with POSSIBLE metastases; as a matter of fact, it might accelerate metastases for prostate cancer.
You might add Atelvia and Actonal to your list.
Back to Prolia (Denosumab): FDA approved for men on ADT and no indication of bone metastases. Though NOT approved for THAT purpose, there are studies indicating that Prolia (and Xgeva) MAY slow down development of metastases.
Anybody in here on Prolia? Side effects?
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Post by Tony Crispino on Aug 18, 2014 22:01:14 GMT -8
Wolf, I fully understand that they are not the same. Prolia/Xgeva and Zometa are more along the lines of men on HT with metastatic disease. Fosamax is more commonly prescribed when men that are not confirmed metastatic and on HT. Also keep in mind there is a very big difference in cost. Prolia and Xgeva are about $1,650.00 per month. The cost of generic alendronic acid is about $50.00 for a 3 month supply and it is an effective bisphosphonate. Many patients may not have access to the more expensive options to protect their bones. In Allen's example above he is asking: "Should Zometa (or Xgeva[Prolia]) as well as docetaxel (as per the CHAARTED study) be started along with ADT as soon as possible when PC with bone mets is diagnosed?" This is a tough question to answer. I would say if the patient has the kind of Mets outlined in the CHAARTED trial that showed that patients with extensive mets the answer is possibly yes. But if the patient has the low volume mets that were inconclusive in that trial then....not so sure. Remember in that trial those patients were inconclusive at the median of 5.6 years as they were mostly still alive. That is a very long time to be on any bone drugs that have been known to cause ONJ. In that case it may be better to have them on a bisphosphonate. I clearly do not know but I can ask. Clearly a question that an answer for each case may be different. Denusumab Side EffectsWe have a long history with the bisphosphonates. But denosumab has only been approved since 2010. I'll keep my eyes open for when men are on that drug for more than 5 years. It can certainly go either way for long term use. |
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Post by Allen on Aug 18, 2014 23:31:20 GMT -8
Tony- The outcomes are exactly opposite. The outcome in question is not survival, but a delay in the time to first SRE and PSA failure. - • In the Okegawa randomized clinical trial (RCT), 42 of the 105 men in the ADT+Zometa group (40%) had PSA failure (median time 37 months) vs 46% in the ADT-only group (median time 20.5 months), and the difference was statistically significant with that sample size (p=.004). The difference in the time to first SRE was even more impressive: it was not reached for the men taking Zometa vs 60 months for the men who did not (p=.044).
• The Kamiya RCT similarly found "The addition of zoledronic acid to combined androgen blockade showed prostate-specific antigen and bone turnover markers response compared with combined androgen blockade therapy only, suggesting a potential antitumor effect of zoledronic acid in the management of metastatic prostate cancer patients."
• The Ueno RCT, found "the use of ZA at the beginning of hormonal therapy have not only a preventive effect on the occurrence of SREs but also a relapse-delaying effect."
• The Uemura study did not have a randomized control group, but used a non-randomized control group of patients at the same institution. I agree that it's not as rigorous as the other RCTs, but the findings were similar.
Altogether, these Japanese studies have a combined sample size of 424 vs 645 in the Alliance trial. I don't think the Alliance trial overwhelms a meta-analysis of the Japanese studies by any means. My question based on the CHAARTED study wasn't about docetaxel, it was about when to start Zometa (or Xgeva) in the setting of mHSPC. Alliance says no benefit to starting earlier, the Japanese studies say to start immediately. To twolf's comment... there are two separate issues. One issue is how best to use any bisphosphonate to prevent osteopenia and osteoporosis in men taking ADT. A separate issue is how best to use Zometa or Xgeva to prevent skeletal-related events (fractures, pain, spinal compression) that result from bone mets. |
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Post by lowroad on Aug 18, 2014 23:34:22 GMT -8
Allen,
please have a look at the ZEUS Study, where Dr. Philip Saylor noted:
“The ZEUS results affirm that we are well served to reserve the use of potent osteoclast inhibition — with either zoledronic acid or denosumab — for men with prostate cancer that is already metastatic to the bone and has progressed on first-line androgen-deprivation therapy”
Giving Zometa or Denosumab (Prolia/Xgeva) longer than 5 years may increase the adverse effects: ONJ, like Tony brings to our attention.
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Post by Tony Crispino on Aug 19, 2014 0:05:20 GMT -8
Allen, To be clear I am not tying the use of docetaxel with the use of osteoclast inhibitor drugs but rather responding to your question as to whether starting Zometa, or as Wolf points out, other osteoclast inhibitors in accordance with the CHAARTED eligible patients. Seeing that the CHARRTED trials gives us great data on metastatic patients surviving beyond 5 years, is my point. That is the clear warning on the drug labels for Zometa and denosumab. Earlier use may produce good effects on the Japan trials, but do the benefits outweigh the harms? That is why I linked the side effects of denosumab and they are not too different for Zometa. For reference: Zeus Reported results
Various articles on Denosumab
I have sent a "big guy alert" to possibly comment. |
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twolf
Junior Member
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Post by twolf on Aug 19, 2014 10:05:08 GMT -8
Tony, You seem a bit confused about Prolia. It is specifically approved by FDA for men WITHOUT metastases. As for the cost: not $1,650/month, but $1,650/year! From www.todaysgeriatricmedicine.com/archive/110310p6.shtml : "Cost could be seen as an obstacle for patients considering Prolia as a treatment option. While generic Fosamax costs roughly $100 to $200 per year and brand-name bisphosphonates slightly less than $1,000 per year, Prolia will cost about $1,650 per year plus the cost associated with an office visit. Prolia is also more expensive than Reclast, which costs $1,100 for a yearly dose." As for lowraod's comment: I was told that Prolia is limited to 2 years (4 6-months shots), but I can't find this in the literature. My personal interest: my endocrinologist wants to put me on Prolia after Boniva, Actonal and Atelvia didn't result in a noticeable increase in my bone density. (I am in my first ADT off-cycle for 3.5 years). |
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twolf
Junior Member
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Post by twolf on Aug 19, 2014 10:05:55 GMT -8
Tony, You seem a bit confused about Prolia. It is specifically approved by FDA for men WITHOUT metastases. As for the cost: not $1,650/month, but $1,650/year! From www.todaysgeriatricmedicine.com/archive/110310p6.shtml : "Cost could be seen as an obstacle for patients considering Prolia as a treatment option. While generic Fosamax costs roughly $100 to $200 per year and brand-name bisphosphonates slightly less than $1,000 per year, Prolia will cost about $1,650 per year plus the cost associated with an office visit. Prolia is also more expensive than Reclast, which costs $1,100 for a yearly dose." As for lowraod's comment: I was told that Prolia is limited to 2 years (4 6-months shots), but I can't find this in the literature. My personal interest: my endocrinologist wants to put me on Prolia after Boniva, Actonal and Atelvia didn't result in a noticeable increase in my bone density. (I am in my first ADT off-cycle for 3.5 years). |
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Post by Allen on Aug 19, 2014 10:53:18 GMT -8
Well, another RCT was published today in Lancet Oncology that argues for earlier use of Zometa in high risk men, in contrast to the ZEUS and Alliance studies. In fact, it found a benefit to use before mets were detected. Study details:• 1071 men with no mets• locally advanced PC, defined as [GS≤7 and T2a and PSA≥10] or [anyone with T2b or higher] • diagnosed 2003-2007 • median follow-up 7.4 years • randomly stratified into 4 treatment groups: (1) STAS - short term (6 months) androgen suppression before radiation (control group) (2) STAS+ZA - short term (6 months) androgen suppression before radiation plus 12 months of Zometa (3) ITAS - intermediate term androgen suppression= STAS+ 12 months adjuvant ADT (4) ITAS+ZA - ITAS plus 12 months of Zometa Results:
| PC Mortality | All Cause Mortality | PSA Progression | Local Progression | Bone Progression | Distant Progression | Secondary Therapy | | STAS | 4.1% | 17.0% | 34.2% | 4.1% | 7.5% | 14.7% | 25.6% | | STAS+ZA | 7.8% | 18.9% | 39.6% | 6.1% | 14.6% | 17.3% | 28.9% | | ITAS | 7.4% | 19.4% | 29.2% | 1.5% | 8.4% | 14.2% | 20.7% | | ITAS+ZA | 4.3% | 13.9% | 26.0% | 3.4% | 7.6% | 11.1% | 15.3% |
The only differences vs STAS alone that were statistically significant are marked in bold. The authors also found that the lower rate of PSA progression and secondary therapy among the ITAS+ZA men was attributable only to men with GS 8-10. They found that ZA conferred no added benefit to intermediate term androgen suppression among men with GS 7 or less. So this study suggests a benefit to adding Zometa to longer term ADT for men with high grade tumors even before mets are detected. There seem to be many contradictory findings across studies. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial |
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Post by Tony Crispino on Aug 19, 2014 14:01:13 GMT -8
Well two posts to respond to, so two posts I shall make. First Wolf's post, Two points ~ Denosumab cost, and FDA approval for its use. The information I have on either Prolia or Xgeva is identical. According the the Prolia Website, the whole price of Prolia is $ 825.00 for a single 60mg dose. According to the NCI Website on FDA Approval for Denosumab, the drug at this time is only "Approved to increase bone mass in patients at high risk for fracture including androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer." in 60mg doses every 6 months. And... The only other approval of Denosumab is for men with metastatic prostate cancer whose disease is hormone refractory in 4-week doses of 120mg ($1,650.00 wholesale) At least according to the Prolia website, my cost is correct. In addition there are administration costs. The Prolia site goes on to say the prices may vary and a chart is provided on what patients actually pay for the drug minus the administration (60mg doses):  How much the patient pays varies by coverage by their carriers. If the drug is used off label I do not know if the patient is responsible for all costs depending on approval by their carrier. If any other data exists that show us differently than the Prolia website and the NCI websites, please let me see it. With programs like the one below the patient will recieve a small portion of the costs and the carrier will pay whatever the negotiated price is. According to this press release by Xgeva the costs are identical to Prolia. I did find however this from Xgeva: First Step Program
XGEVA® patients - Patient must be commercially insured.
XGEVA® FIRST STEP™ Program
Help your eligible commercially insured patients meet their OOP costs†
No income eligibility requirements
$0 OOP cost for initial dose
$25 OOP cost for subsequent dose‡
Program covers out-of-pocket XGEVA® costs only up to $5000.00
Program does not cover costs related to office visit, physician, staff, or administrative charges associated with administering XGEVA®. Other restrictions may apply
‡Total program benefits may not exceed $5,000 per patient per six month period as defined by the program. Patient is responsible for costs above these amounts.
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Post by Tony Crispino on Aug 19, 2014 14:25:43 GMT -8
Allen,
You are right. There are contradictory findings across the studies. For now it seems you'll need your doctor to check the box that says "High Risk for Fracture Receiving ADT for Nonmetastatic Prostate Cancer" to get two 60mg shots per year. I assume that approval has set the dosage to reduce adverse side effects as a non-metastatic case could be on the regimen for decades and that is simply risky according to the FDA approval rejections for early use I linked from the Infolink previously.
I hope Nick replies. His take will be interesting.
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Post by Allen on Aug 19, 2014 16:43:04 GMT -8
Just some perspective. While there is a risk of osteonecrosis of the jaw with ZA and Xgeva, and the risk seems to increase with increased dose and length of use, the risk is in the range of .7% to 12%. The median # of infusions associated with it is 35. The risk is reduced by having dental work done before treatment. The risk is higher if one wears dentures. Vigilance is key. It is a potential low-incidence side effect of treatment to be aware of and weigh against the benefits. Bisphosphonate-Related Osteonecrosis of the Jaw: Historical, Ethical, and Legal Issues Associated With Prescribing |
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Post by Tony Crispino on Aug 19, 2014 16:59:20 GMT -8
Great paper Allen,
I wonder what the results are for a patient that has been on Zometa or Deusumab for 10 years? We do know that many patients can live that long with small volume mets as told by CHAARTED. We also know inon-metastatic patients likely will live that long ~ even longer. Of course the discussion then comes up, should the non-metastatic guys even be on HT that long?
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Post by Tony Crispino on Aug 19, 2014 18:16:34 GMT -8
Question for Wolf...
When do you see your endocrinologist? I hope the best for ya there. Let us know how that goes.
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twolf
Junior Member
Posts: 16
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Post by twolf on Aug 20, 2014 16:50:34 GMT -8
Sorry to prolong the Prolia discussion. Tony you seem to equate Prolia and Xgeva. They are not the same. They are both Denosumab based, but given in different dosages. The press release you quote is for Xgeva only, NOT FOR Prolia. Your original quote: "Prolia and Xgeva are about $1,650.00 per month." Absolutely not true as Prolia will be given only every 6 months. Look at this website: reference.medscape.com/drug/prolia-denosumab-999566"Androgen Deprivation Induced Bone Loss Men with prostate cancer: 60 mg (Prolia) SC every 6 months" "Skeletal-Related Events Prevention of skeletal-related events (SREs; eg, bone fractures and pain) in patients with bone metastases from solid tumors." Xgeva: 120 mg (1.7 mL) SC every 4 weeks" So, with the $825/shot quote for Prolia and 2 shots of 60 mg per year the cost for Prolia is $1,650 PER YEAR. Xgeva is administered monthly with a 120 mg dose at $1,650 PER MONTH. I am awaiting a call from the endocrinologist for my first Prolia shot. |
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Post by Tony Crispino on Aug 20, 2014 21:32:24 GMT -8
Wolf I stand corrected.
Both products are made by Amgen and in their papers they discuss the use of Deosumab on both applications without that distinction difference. In either case the administration costs remain the same over and above the cost of the drugs.
However the noted side effects over a long use of either remain a consideration.
And you are welcome to prolong any discussion here...
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