Erleada vs. Xtandi: onclive.com/view... - Advanced Prostate...
Erleada vs. Xtandi
Erleada is good stuff, although it has some annoying SEs.
For men who are castration-resistant, a trial (ACIS) combining Zytiga and Erleada (+ADT) found there was a benefit in radiographic progression-free survival (rPFS) to combining the two drugs. rPFS was extended 6 months (from 17 mos. to 23 mos.) by the combination compared to Zytiga (+ADT) alone. With median follow-up of 55 months, there was no significant difference in overall survival. Unlike Xtandi, Erleada reduces androgen receptor expression. Combining Xtandi and Zytiga was found to have no benefit over Xtandi alone.
janssen.com/janssen-present...
When they found that combining Xtandi and Zytiga had no benefit over Xtandi alone I was surprised. Why is this do you think?
I don't know - I was disappointed, as I often am when therapies fail. The only important lesson is that that combination doesn't work. So we move on and try some other combination or sequencing.
If there was no significant survival advantage after 55 months with Erleada and Zytega together, doesn’t that mean it didn’t help even tho the rPFS was better with the combination?
Schwah
Frequently when this happens, it means that the patient has a harder time with side effects and dies of other causes at a rate that makes up rPFS. There are other possible reasons and the study goes into some of them.
No. rPFS was the primary endpoint- which means that the sample size was large enough ("powered") to detect a statistically significant difference in rPFS (with <5% error and a meaningful difference) . The trial was not powered to detect a statistically significant difference in overall survival in that time period. The median overall survival was 36·2 months for the combo vs 33·7 months for abiraterone - with this sample size, that difference was not statistically significant. In other words, the sample size was insufficient to compensate for the false negatives.
A couple of years ago, the FDA signalled that it would accept a surrogate endpoints, and not just overall survival. (This was how Nubeqa, Erleada, and Xtandi were approved for non-metastatic CRPC). This gets the drugs to patients sooner, saves costs, and gets more trials completed (many trials are abandoned because of lack of accrual).
I know that the FDA did that and I wasn't pleased. OS is more important to me than CSS or rPFS. That's the approach of some doctors. If you don't die of PCa it is a victory for them. If you die of diabetes/dialysis or a heart attack it's too bad but you didn't die of PCa! I've had this discussion with more than one MO. Fortunately, my MO agrees with me. She's a very practical person. Great fit and we actually sincerely like and respect each other (or she's a good actress).
So I try to read between the lines to get at what OS might be. I understand that this is not what the FDA condones and not the way they set up the new rules. But it's my cancer and my life and fortunately, the FDA isn't controlling how I interpret studies.
I would like two RCT stage "endpoints" if you will. rPFS or CSS but also OS.
The way they get to surrogate endpoints is they first prove that it is highly correlated with overall survival. That's why the FDA approved it. Because there are so many life-extending therapies now, it is hard to say what caused an increase in overall survival, unless it was the last therapy used.
Just what you die of when you die with prostate cancer can vary. Cancer increases blood clots, so stroke, heart attacks, or pulmonary embolism may be the proximate cause of death. So may opportunistic infections because the bone marrow has been compromised. Loss of kidney function is often noted.
But randomization is what irons out all the various causes of death. However, when there are many therapies given after the trial (as in ACIS), and patients were not restricted in future therapies, how can you attribute deaths to the earlier therapy? Some RCTs (e.g. VISION) do follow-up studies to help determine if there was an effect of later therapies. Cancer biology is also a confounder, which is included in some newer trials.
I did know all of this info but still did not agree with the decision. I assume that I am not alone. I would consider 0.7 a rather moderate correlation.
Most doctors and patients I know are thrilled to have the drugs sooner. You may be alone.
I think you know by now that I am more than okay with being in the minority.
But I am curious what my MO thinks - I'll put it on my list of questions for next month. Not actionable but I'd like to hear her pro/con thoughts. I keep saying that she is smart and practical. And she is very good at looking at all sides of an argument and doesn't seem to view things as black and white so I value her opinion. Love that lady!
So are you saying that the greater rPFS is sufficient evidence to the FDA (and in your personal opinion) that it will also extend lives? If not, what’s the point?
Schwah
Yes, it is highly correlated with overall survival. It enables earlier availability of the drugs, lower sample sizes, and reduced costs.
Look into 0.7 correlation. You can also calculate correlations of data with a correlation calculator (or just formulas and I think that excel might even have something).
Good question. Good discussion of rPFS, OS here urotoday.com/center-of-exce...
I wonder why they didn't speculate on this:
"Cause-Specific Survival
Cause-specific survival is an important term in clinical studies and refers to the number of people surviving a particular cancer after a period of time.4 An example is the easiest way to describe this. Whereas overall survival from lung cancer includes not only those people who die from lung cancer, but also heart disease, other cancers, and any other condition, cause-specific survival refers to only the likelihood that someone would survive lung cancer alone. This is important in evaluating potential treatments. A theoretical strong drug which damages the heart may increase cause-specific survival from lung cancer but could actually lower overall survival rates due to deaths from heart disease."
It's the first thing that pops into my mind. I take it one step further when looking at therapies. I look at OS and CSS. Even if CSS is greater on a certain therapy, if OS remains the same, I'm likely to look the other way. This isn't always the case, but frequently, it means that the therapy is so hard on you that, while CSS improves, OS is still the same or even lower because you are weaker and succumb to other health conditions at a faster pace. But, regardless of whether or not this is the case, my goal with my therapies is to live longer, and not necessarily to drain my pocketbook faster in support of the medical industry. And in the end, if I die of kidney malfunction, is it really so much preferable to dying of cancer?
Well said. I wish all practicing doctors understood it as well as you do.
I was rejected by insurance company for Erleada. Now I am wondering if I should have paid out of pocket. I have been on Xtandi for a couple of months. If Xtandi fails when I become CRPC is Erleada a treatment option down the line? Insurance will pay for Erleada if Xtandi doesn’t work.
If Xtandi is working, why change right now?Xtandi is kind of neat with BAT. Most guys who become resistant to Xtandi can do BAT and become sensitive again.
Clinical trials are underway to see if this can be repeated more than once.
I am watching the BAT trials and hoping for extended life evidence. Thanks for the information on this. It’s a devilish puzzle to figure out.
Some really neat RCTs are being done. clinicaltrials.gov/ct2/show...
My personal experience with BAT (I am not CRPC) is that it works great for me. Been 7 months now and my PSA reliably goes to 0.2 and then drops to <0.1 during each cycle. I started BAT when my PSA was 0.17. So, whatever happens, as long as I bail when it goes above 0.2 I count it as a win for postponement. I took the approach that trials are trials. I can get clues from trials. But the only way to really test it on me would be to test it on me. I was good with the risk though and it is DEFINITELY not for everyone - if my dad was still here and had PCa I wouldn't want him to try my modified BAT.
I appreciate the link. Your risk analysis gives me something to think about. I will get my MO’s opinion on this and discuss this trial with her. Best of Luck and thanks for the updates.
Erleada -- and this could've been any other 2nd Gen hormone therapy -- helped morph my low grade cancer into squamous cell carcinoma. Not good. My PSA was showing 0.2 but the rest of the squamous cell was being unexpressed through PSA. Another pathway: cancer.gov/news-events/canc... .
Xtandi vs Orgovyx
Zytiga vs Xtandi 
Xtandi vs. Abiraterone vs. Nubeqa
Zytiga vs. Xtandi vs. Radium 223 vs. Cannabis
Can Erleada/Apalutamide and Xtandi/Enzalutimide be used subsequently or is Xtandi ineffective after Erleada stops working?
