I now have non-metastatic castrate-resistant PCa (MO CRPC). Recurrence after radiation & Lupron. High-risk; highly aggressive; Gleason 8.
Tried ADT (Eligard); gave out after 8 months (March-Nov. 2019). Now on abiraterone & prednisone (plus Eligard); PSA rising; will probably try another drug.
I'm thinking of the new receptor-inhibitors: apalutamide, darolutamide, enzalutamide. Tests show they extend metastasis-free survival by 36-40 months. But my doc says no; says they'd have only a 10% chance of working!
He didn't specify a drug; seemed to lean toward chemo. As MO CRPC, is it really time for that? And what's wrong with the receptor-inhibitors? "Read the CARD study," he said.
I did. It said cabazitaxel works better than abiraterone or enzalutamide -- for those previously treated with docetaxel. Doesn't apply here -- unless we go directly to chemo.
Long story, but: Have any of you with CRPC but no mets skipped the receptor-blockers & gone right into chemo? Do apalutamide, etc., have hidden flaws? What treatments have you tried, & with what results? Many of you know chemo side effects all too well; I'm scared & want to postpone it as long as possible.
I'd very much welcome your advice! -- yeatz
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yeatz
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Abiraterone & the 'lutamides' work in different ways, but the target in each case is the androgen receptor [AR] axis, & common resistance mechanisms are largely the same. Sadly, for most men, there is little or no benefit in using the drugs in sequence.
"Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide)."
as you say, you have never received Docetaxel. However, the study compared Cabazitaxel to Enza/Abi in men previously treated with Abi/Enza, respectively, & there was some benefit even though Cabazitaxel & Docetaxel are both taxanes.
"a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients" [Cabazitaxel versus Enza/Abi].
***
Have you read up on the BAT [bipolar androgen therapy] studies of Sam Denmeade at Johns Hopkins? There have been a number of threads on BAT here.
Thanks for your reply. I had the impression, from NCCN & the tests, that abiraterone had a very different function than the litamides. It's designed to prevent the creation of androgens from cholesterol anywhere in the body -- especially the PC cells. The literature on it doesn't suggest that its main function is to target the receptors. If I'm wrong on this, please point me toward the evidence; I'm new to being CRPC and have
an open mind on all this.
Hadn't heard of the BAT study; I'll certainly check it out. I appreciate your telling me about it.
When Abi & Enza came on the scene, the question that arose was - which sequence was best - Abi before or after Enza? Either way, the 2nd drug was often a failure in that situation. A number of experts said that they were not surprised since the target was the AR axis. The drugs were essentially doing the same thing, even though it might not seem so. It has been shown that there is no benefit in taking the drugs at the same time. They are both very good at what they do - which is to prevent AR activation.
Abi, just like the castration drugs (or castration itself) seeks to starve the AR of androgen. Enza blocks androgen access to the AR. Naturally, resistance responses such as the splice variants (e.g. AR-V7) are common in those who have failed either drug.
As you know, 3 advanced anti-androgens have recently been approved for non-metastatic (M0) CRPC - Nubiqa, Erleada, and Xtandi. Nubiqa is especially interesting because it may cause less fatigue. Why does he say it only has a 10% chance of "working" and what does he mean by "working"? In the Darolutamide trial, for example, metastasis-free survival was increased by 69% (an advantage of 32 months: 40 months met-free in total), and even the low end of the 95% confidence interval (34 months until a met was detected) was a year longer than the placebo (22 months until a met was detected). What's more, the advantage held even in heavily pre-treated patients (most of the patients in the study had already received two or more previous hormonal therapies).
The only open question is whether it will increase survival.
I am usually a big fan of early docetaxel treatment. It has been proven to increase survival in all metastatic men (those with mHSPC and those with mCRPC). The earlier it was used, the longer the increase in survival, and the milder the side effects (in fact, when used among newly diagnosed men with metastases, the number of serious side effects was no different whether treated by docetaxel or Zytiga). A recent subgroup analysis of STAMPEDE showed that early use (while HSPC) of docetaxel in non-metastatic (M0) men did improve failure-free survival and progression-free survival, at least for several years, but did not improve overall survival.
Unfortunately, I haven't seen any docetaxel data in the group you are interested in (M0 CRPC). I would reason (always dangerous!) that it would not provide any overall survival advantage in your situation either (because earlier is always better for survival), but it might still slow progression. Whether docetaxel or Nubeqa is better at slowing progression, I cannot say.
He has only briefly been on Eligard and Zytiga before they failed. Darolutamide prevents androgen receptor amplification (Zytiga does not)and may "work" where the others failed. Remember that all the patients on the trial had failed GnRH agonists, and most had failed Casodex on top of that. I'd be far more concerned about whether there is any real benefit in terms of increased survival. He has little to lose in trying it, since docetaxel isn't likely to do much for M0 anyway.
Thanks for your reply. Your reading of the lutamide studies coincides with mine. If my PSA keeps rising & my doc suggests chemo drug, I'll press him on why the new
receptor-inhibitors wouldn't work for me.
On lowroad's reply, ALL the lutamide studies compared new drug with placebo -- so of course they excluded recipients of others.
On pjoshea13, I thought abiraterone didn't target the AR's like the lutamides; its function is to stop production of androgen from cholesterol anywhere in body -- especially by the PC cells.
Guess I should reply to them -- or maybe issue a new post on this.
Your terminology is getting in the way of what you're trying to say. I don't know what you mean by "lutamides." Darolutamide and bicalutamide are both "lutamides." Yet they have very different properties. Do you mean advanced anti-androgens (Xtandi, Erleada, or Darolutamide) or all anti-androgens (including bicalutamide, nilutamide, and hydroxyflutamide)?
Cool. Nubeqa, Erleada and Xtandi for M0CRPC were tested along with a GnRH agonist/antagonist and compared to a placebo + GnRH agonist/antagonist only .
The only trial that included an first-generation antiandrogen (+ADT) in the control group was the ENZAMET trial of Xtandi for M1HSPC.
I don't agree with the philosophy of "using up" anything. I think it is best to deploy the biggest guns available while they are able to provide the most benefit, which is sooner rather than later. This is especially true of Nubiqa and Erleada because this is the only time that someone in your situation (M0CRPC) will be able to get them. After you progress to M1, you will no longer be able to get either (except in a clinical trial).
The data do not show that enza fails immediately after abiraterone - it just works for less time (unless you have some rare mutations like AR-V7). And, that data is not based on men in the M0 situation; however, given your short stint with Zytiga, I don't expect it will work for very long. Both Nubiqa and Erleada prevent AR amplification, and may work longer (cross resistance is unknown for them) - you won't know unless you try them, and this is your only chance to try them.
As I showed you, there is reason to be skeptical that chemo will work for you in the M0CRPC situation, since it confers no benefit in the M0HSPC situation.
After you progress to M1, chemo is known to have benefit, and it may reverse resistance to enza. There will also be several therapies, approved and experimental (e.g., Provenge, Xofigo, BAT, Lu-177-PSMA, CAR-T, BiTE, etc.) that you currently do not qualify for because you are non-metastatic.
Tall_Allen -- A follow-up to our April 16 conversation:
You said that as an MOCRPC, my only chance to try Nubiqa or Erleada would be now; after you progress to M1, you can't get either (except in a clinical trial).
I'm wondering: Why can't you get them once you're an M1? What would prevent a doc from prescribing them? Is this the standard of care used somewhere -- and if so, who issued it? Would Nubiqa or Erleada interfere with chemo drugs?
The NCCN Guidelines list apalutamide, darolutamide, and enzalutamide as the "preferred regimens" for MOCRPC. For M1, their "preferred regimens" are the chemo drugs: docetaxel, cabazitaxel, etc. That certainly fits the pattern.
But they do say that "all secondary hormone options listed above are allowed" for M1, and specifically refer to the list that includes those three lutamides.
I'm asking because your advice makes a lot of sense, and I plan to follow it: resist chemo, and press for darolutamide or apalutamide. If there's a specific policy that says it's now or never for dar. & apal, that would strengthen my argument.
The doctor can prescribe anything he wants, whether approved or not. However, insurance will usually only pay for drugs that are FDA-approved for a specific indication. Darolutamide is only FDA-approved for M0CRPC. Apalutamide is FDA approved for M1HSPC and M0CRPC. Those are the only two hormonal drugs currently approved for M0CRPC. Neither is currently FDA-approved for M1CRPC.
The only two advanced hormonal drugs FDA-approved for M1CRPC are abiraterone and enzalutamide.
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