Let me answer your questions in a slightly different order, if you don't mind..
1. Is the control arm in this trial (one year of degarelix only followed by a vacation) within the standard of care? Would ADT ordinarily begin at a PSA level of only 0.5-1.0 ng/ml? Does doubling time play any role in when doctors recommend ADT?
The standard of care has always been to begin ADT when any of 3 events occurred after curative options have failed:
1. metastases are detected
2. PSA is high
3. PSADT is rapid
You don't qualify by #1 or #2, but to get into this trial, you have to have a PSADT<9 months, so the control arm is within the standard of care. The thinking is that each of those three indicates metastases somewhere, even if they are currently too small to be detectable.
3. Tall Allen commented in a thread last year that “[a]nything [referring to clinical trials] with ARN-509 (Apalutamide) is very interesting.” I’d be very interested to know what TA thinks about this particular trial. I gather that some oncologists operate on the theory that it is good to hold some drugs in reserve for when standard ADT fails. This study is testing the opposite hypothesis: hit hard with multiple drugs right at the beginning. How "interesting" is this?
So, based on my comment above, I certainly do think this is an interesting trial and worth pursuing. What makes it even more interesting are the recent STAMPEDE and ATTITUDE trials. I realize they only showed a significant benefit in metastatic men. You're not detectably metastatic, but with your rapid PSADT, there's most likely something somewhere.
The logic behind "holding something back" escapes me. If it improves overall survival, how can anyone argue against using it? We saw that with docetaxel in polymetastatic mHSPC, overall survival increased by 17 months vs only 3 months if they waited for mCRPC. I suspect that will be true of these hormonal agents too. In the future, there will be new medicines (darolutamide, for instance).
2. How strong is the evidence that intermittent ADT is as effective or nearly as effective as continuous ADT? In this study, the control arm, like the other two arms, gets one year of treatment before going into a follow-up phase until the disease “becomes worse.”
Almost all the trials of intermittent vs continuous show there is no difference in overall survival. The exception may be when the patient is already detectably metastatic. What I found to be interesting in this regard is the TOAD trial. The patients had to be non-metastatic and recurrent (there was no PSADT qualification) and the vast majority went on iADT. So far we have only 5 years of f/u which isn't nearly long enough, and I wish they had recruited more patients (what you wrote in #5 is so important!). But I drew a few interesting conclusions from it:
• Killing off the hormone-sensitive cells earlier, and reducing their load, seems to trump the effect of selecting for castration-resistant cells.
• While the effect on survival was minor in just 5 years, the effect on mortality was significant — cut in half! That tells me that there are at least some men (perhaps those with significant comorbidities?) who may live longer if the systemic intervention is started sooner rather than later.
• The vast majority of men in TOAD were started with intermittent hormone therapy, and hormone therapy may have meant anything from a few bicalutamide pills a week to full-on ADT3. But on the average, their quality of life was not diminished by starting earlier. So that means that the symptoms of the disease came to outweigh the symptoms of iADT, or that the symptoms were not burdensome.www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00107-8/abstractwww.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30426-6/abstract
4. Are there other trials I should consider before committing to this one? I’ve searched clinicaltrials.gov, but I am not sure I’ve searched well enough. It appears that not too many trials are geared to my profile of non-metastatic, castration-naïve PCa after failed SRT. This trial is probably my best, if not only, shot at getting apalutamide this early in my journey. Just how exciting is apalutamide?
I'm amazed you even found this one. Clinical trials for non-metastatic, recurrent, hormone-naive HSPC are few and far between.
How exciting? Well when used on men with non-metastatic CRPC, 89% saw their PSA drop > 50% and the time to PSA progression was 24 months. That compares to 11 months for Zytiga in mCRPC.
But on the other side of the balance sheet, toxicity is not exciting. Both Zytiga and apalutamide carry risk of adverse effects - most are not serious, but some are. And combining the two may increase toxicity to an unknown degree. Before agreeing, I think it's prudent for you and your doctor to review the known side effects, especially in light of your own medical history.
4. I am motivated to participate in the trial not only because the experimental drug combinations may help me (if I am assigned to one of the two arms with the experimental drug combinations) but also from a desire to contribute to the science that may help others. On the other hand, if I agree to participate, I could be facing the side effects of as many as four drugs for the next year and will need to undergo tests and medical appointments that otherwise would not be necessary. It is also possible that the drug combinations will accentuate side effects in ways that severely impact my quality of life.
Your desire to help others is admirable. TOAD RCT, mentioned above, did not meet its recruitment targets, and we're all the worse for having less definitive data. I think that the closeness with which you are watched on a clinical trial is one of the benefits. You get a level of care you might not ordinarily get, and the doctors are eager to hear about
every ingrown toenail. Yes, the extra meetings are a hassle, but you will be well cared for. I agree about
the side effects - we have no idea what the SEs will be like in combining them. However, because you are so closely watched, I would hope they would catch anything before it becomes too serious. You can drop out at any time.