In the CHAARTED trial, metastatic burden was divided into low burden (4 lesions). CHAARTED’s criteria seems to have become the standard for evaluating how metastatic burden affects choices of treatment and outcome.
I bring up the metastatic burden, because I could not find a clinical trial where ADT+AAP (Abiraterone +Prednisone) did not offer a superior outcome to ADT+D (Docetaxel) in 70+ year old patients with a low metastatic burden. When QOL is factored into the equation, the choice seems overwhelming.
I began this journey in December following the Peace1 “triple therapy” approach ADT+AAP+D. After completing my 1st cycle of Docetaxel, my MO took me off AAP and reduced my dosage of Docetaxel because my liver enzymes elevated. Effectively, I am on a treatment plan that matches the CHAARTED trial of ADT+D.
The CHAARTER, GETUG15, and STAMPEDE clinical trials confirm that I will derive a benefit from ADT+D, but there doesn’t appear to be any benefit that is greater than ADT+AAP.
I have completed 3 cycles of Docetaxel (3/4 dose). Is there any reason that I should continue beyond the 4th cycle? My preference is triple therapy. But, if I can’t continue on triple therapy ( Darolutamide has same enzyme issues), what do I lose by stopping Docetaxel and returning to ADT+AAP?
Thank you warriors! This experience is truly drinking from a fire hose.
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TMcgee
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Why not resume your triple therapy when the chemo is finished by restarting the ADT and AAP (or Daro)? So still triple therapy but one part gets postponed. I don't think it is that uncommon for the treatment to be adjusted depending on your response, particularly for the chemo part. But not sure what the impact of that is on treatment effectiveness or if it has been tested. I just finished 6 cycles of chemo last week and am on a similar regime.
I think that you are stictly speaking correct but not every case fits exactly in a neat box and I guess that's where the oncos earns their money. My own case is BCR after RP and the treatment regime is essentially "triple therapy" with Doc + ADT + Daro. My onco, who is a teaching professor, explained that not everything is exactly covered by a trial and it is sometimes necessary to draw inferences as to what is the best treatment in each case even if not exactly by the book. Keep drinking from the firehouse followed by a stiff glass of whiskey.
Forget about all this stuff, your Bio ends with you off to ski in France. I want to read about the trip! 😁
Your teaching professor is spot on. I’m over seventy. But, I don’t have hypertension, obesity, diabetes or any of the co-mobilities that skew the statistics. It is evident to me that the drug maker wants trials with young healthy metastatic participants, despite the fact that most of the patients are old and already sick.
I would have been depressed of I didn't get out skiing this season so it had to be done. Next up is 8 weeks of RT starting in three weeks time. I am also on ADT for 3 years and they will add second level hormone therapy which I think is Darolutamide (to be confirmed). My onco wanted to give me a few weeks to recover from the chemo before starting on more hormone treatment. Fun and games.
TA appreciate your feedback. Regarding the question of synergy, isn’t the loss the same if I stop AAP? This really is the critical question. My Mo believes Docetaxel is the primary driver for a deep remission; but, I can’t find any evidence to support or contradict his assertion. AAP and D appear to be of equal importance for my situation. Why subject myself to the extra side effects, if no benefit?
Right now, I am trying a 1/2 dose of AAP. If my enzymes remain in range, I will definitely continue with all three therapies.
I agree with your MO. D only works on rapidly dividing cells and will be useless once abi drives your cancer into senescence. Now is the time to use docetaxel. I have no idea why you think there is no proof of benefit, when that is exactly what ARASENS and PEACE1 proved.
I must not have made myself clear, I believe there is a substantial benefit to Docetaxel; but, in my situation (low burden and over 70), there is no evidence that ADT+AAP will not achieve the same end points as ADT+D.
Caveat: A follow-up Peace1 study indicted that an over 70yr old could achieve the same end points as the under 70yr old, if they could tolerate the triple therapy.
TA: the discussion that you highlighted in the 2nd link is what started me asking the question of medication. I watched a Dana-Faber video “is there still a role for Docetaxel in mHSPC?” Up till this week, I have ignored metastatic burden and cheated on my age. The more therapy the better! I’m not very smart.
The success of triplets short-circuited the discussion of docetaxel in low metastatic burden (although IMO, STAMPEDE makes a stronger case than CHAARTED). And ARASENS proved that the triplet is a benefit even for low metastatic burden (PEACE1 isn't mature yet for that subgroup).
In all honesty, I struggled through all the trials. I discounted all of the results, where the control was ADT (and placebo). I rejected Stampede because it failed to achieve the 95% CI.
Keep in mind, my hypothesis is “if I can’t be on triple therapy, which two therapies offer the greatest return”? The evidence is overwhelming that if you are young and have high metastatic burden, ADT+D is the best alternative. But, stampede doesn’t prove that if you are old and have low burden, you should be on ADT+D.
I wish that this scenario was a hypothetical; but, so far your comment about senescence is the jewel of this discussion. Part of my challenge is I have a 10,000 ft view as to how each therapy interacts (synergy) with the other therapies. You have raised a point about a dependency that I need to explore. Thank you for that.
"I rejected Stampede because it failed to achieve the 95% CI." I think you misunderstood the statistics. The 95% CI HR for docetaxel was 0.76 (0.62-0.92). You seem to be trying to force subgroup analysis on the trial that it wasn't powered to prove. You can't create a new sub-subgroup of older men with low met burden and draw conclusions- the trial wasn't powered to do that. The error bars get too wide when you do that because the sample size gets too small. What we do instead is look at pre-specified subgroups and judge whether they are or are not sig. different from the overall, and they aren't.
You may be interested in this article that demonstrates the folly of making up new subgroups and trying to draw conclusions:
TA - thanks! Stampede determined that there were no difference between low and high volume results with Docetaxel. But, if you analyze the data, there are 362 total participants in the Docetaxel group; But, if you add the number of observations in the sub-groups, n=333. At the group level, you can’t possibly have a CI 95%; and I would wonder about the randomization. Just to be clear, I’m sure the variance has been easily explained; but, there is a variance so I excluded the results.
STAMPEDE had 724 metastatic patients in the control group and 362 metastatic patients in the docetaxel group. Why would you add subgroups when the total is given? The HR was 0.81, 95% CI 0.69–0.95, which means it is statistically significant.
TA - I didn’t add the sub-groups. The totals are presented at the bottom of the sub-group table. There were only 333 observations; but the metastatic Docetaxel group indicates 362 participants. There are 29 observations that aren’t accounted for in the results. And, as you’re pointing out, the sub-groups and the overall group achieve a 95% CI, which doesn’t explain the missing observations in a randomized trial. Again, I didn’t read the whole trial. I’m sure the discrepancy is easily explained; but, I will bet that for people questioning the low and high volume results, it is a sticking point.
I really appreciate your responses and the value that you bring to all these discussions.
You have to look at the Consort diagram for the reasons for the missing observations. This is really a level of detail that patients needn't concern themselves with. The STAMPEDE trials are probably the best RCTs that have ever been done for prostate cancer and have got some of the best statisticians in the world working on it. It is not a "sticking point." It is just a patient desperately searching for justification. I've studied it carefully and understand the stats, and I can assure you, based on 20 years of studying stats, that the justification you're looking for isn't there.
If I may. In comparison, havent we seen more evidence of using enzulatamide + ADT, in this situation, compared to Zytiga and Darolatamide with ADT - that Docataxel is secondary when Xtandi fails. I also have seen data that show advantage to using Lupron over that other stuff.
Lupron is always used. For doublets, abiraterone, enzalutamide, and apalutamide can be used - no evidence that any one is better. For triplets, with Lupron and Docetaxel, either abiraterone or darolutamide is indicated.
TA - after our discussion about Stampede, I took the time to research the discrepancy between the total patients taking Docetaxel and the subgroup totals. The metadata for table 4 explains that after the randomization 29 patients opted out of the Docetaxel treatment. Those patients were removed from the sub-groups, but kept in the totals (for safety concerns). My concern was regarding the CI=95% for the total Docetaxel group, when 29 patients opted out. The metadata indicates that the total equaled 333 patients, which would explain how the CI=95%
You are right in your conclusions.
Just to explain my interest, I do not understand the medical terminology yet; but, I have advance degrees in Econometrics and have built models for 40 years. I am more comfortable looking at the data than trying to remember all of the different names for Abi (very frustrating).
Good research form is that all patients that go through randomization, called the intention to treat population) are included in the analysis. This prevents researchers from selecting patients that might bias the results.
Both triple therapies had a better overall survival than docetaxel plus ADT, but the triple therapies did not have a better OS than abiraterone plus ADT.
Furthermore, a recent publication about the long term results of the Stampede trial indicates that ADT plus Abiraterone has a median overall survival of 6.6 years.
The Peace 1 and the Arasens trials used mainly ADT plus Docetaxel as control groups. The median overall survival of docetaxel plus ADT in the Chaarted study was 4.9 years, which was the same than in the Arasens trial.
Triple therapies have been adopted as the best treatments . They are more effective than ADT plus docetaxel,
Abiraterone, enzalutamide and darolutamide are very effective. I wonder if any of the triple therapies are really better than ADT plus any of these drugs.
Very difficult they do these studies, meanwhile patients may be exposed to more adverse events.
Funny, your final remarks. I found a study that concluded the average patient is 10 years older than those represented in the trials. There is certain to be more adverse events!
It is clear that the science is catching up to this monster. But, unless I can cure my shortness of breath and fatigue issue, I’m going to be a dual therapy guy and dump the Docetaxel.
Leading up to whichever clinical trial, the control group was ADT+placebo. In the Docetaxel group, you would have ADT+D. Then, when the cycles of Docetaxel are completed, you have ADT until whenever. But, you can’t do that anymore. So, if your control includes two therapies, and your Docetaxel group adds a 2nd gen therapy after the 6 cycles, won’t the hazard risks for the control, Docetaxel, and ADT+AAP all be close to 1?
I understand your quest to successfully get around docetaxel at this point, but TA was pretty clear in his explanation. You also (unfortunately) have experienced the liver issues abi often causes. You also say your health is good for 72, but your shortness of breath and fatigue are driving the desire to remove the docetaxel.
Exercise as always is the metric that matters most with age, magnified as we are increasingly challenged to withstand treatments. How much are you doing and what kind?
London: thank you for responding! My quest is for the best quality of life. Biking and Pickleball are my primary forms of exercise. My truck goes into the garage on Memorial weekend and I bike through Labor Day. It is 7.4 miles to the PB courts, which I trek 6 days a week. I’m a ranked player. I’ll play 2-3 hours a day.
The liver enzyme issue has been a real game changer. I have been confined to the house for 6 days, which translates to 2 /2 months of limited activity should I complete 6 cycles of Docetaxel.
You should be able to get your liver enzyme issue sorted, it is tricky I know.
On ADT we need weight bearing exercise. We need it when we're older already, but the need is exacerbated greatly on ADT due to the muscle loss. Your legs are benefiting from the pickleball and especially the biking, but not enough. The upper body is getting close to nothing, unless there's something you left out.
Again, the ADT induced muscle loss drives the fatigue. Add weights or similar to the good habits you have now and I promise you will see a change in your energy level and more.
it’s never too late to turn that around. Why put all that effort into cycling and a sport only? Even a small amount of lifting makes a huge difference. Keep an open mind!
I wasn’t allowed to enter the mess hall until I reached 10 pull-ups. You’re starting to remind me a lot of Sgt Powell, baddest Drill Sergeant I ever met.
I already hated you! 24? That’s awesome! It’s something that you have to commit to doing your entire life. I truly am shocked at the amount of strength that I have lost. I had to carry a 4x8x3/4 piece of plywood the other day and it was a load. You’ve almost shamed me into it.
I completed my docetaxel when these studies were just being published. I started Abiraterone after my chemo and radiation, (MD Anderson trial) and have remained NED for the last 18 months. I agree that chemo before you completely make everything dormant is a good course, at least for me it was.
First, warms my heart to read that the treatment is working!
I still don’t understand this point, which TA raised. My (very limited) understanding of the treatments suggests that chemo inhibits the cells division, which may or may not cause the cells to die. Then, ADT+AAP (or equivalent) causes the cells to go dormant. As a 72yr old with a low burden, what am I giving up by eliminating the chemo?
I have found one study that argued the incredible cost of the 2nd gen drugs were the sole reason for selecting chemo. I’m very fortunate, as a Vietnam vet I pay very little for any of these drugs.
I did both. Abiraterone wanted to kill me quickly (attacked my digestive system) and Docetaxel tried to kill me more slowly! Neither really worked, Abiraterone did nothing, while Docetaxel did reduce my PSA for a short while for the first few treatments, then became ineffective. Realize this is just one person, not a study...
I wish I could say that, but right now I'm lining up for LU-177, which may be my last hope. PSA is over 250 right now, on stuff that isn't really helping much.
Hi TMcgee. Enjoyed this interesting discussion. Seems you have squeezed whatever insights exist from the best trials of de novo metastatic. Which implicitly mHSPC. Remember none of us is the same as a median patient in any trial and of course we must chart our own individual path. Not just the winds and the currents but also the limitations and capacities of our crafts. (If that metaphor makes any sense.)
So you are partaking of whatever benefit docetaxel can provide at this stage at 3/4 dosage. Depending on how you are handling it you could complete the 6 cycles, or stop at 4. Not sure that 4 is inferior for early treatment. I would stop at the first hint of peripheral neuropathy though.
I tried to get coverage for darolutamide with ADT for my mHSPC recently and was told it would not be covered as I was not currently on docetaxel (though I had it at diagnosis 15 years ago). So you might want to have it prescribed now even though you are favoring AAP. Perhaps your liver might be okay with it?
As for the abiraterone dosing, note that it has been determined that 1/4 dose, 250 mg when taken with a moderate fat breakfast produces therapeutic equivalency (levels) comparable to 1,000 mg on an empty stomach. Perhaps worth considering and discussing. I’ll leave searching for the links on this to you as you are clearly capable.
Would not worry about being past 70, longevity and maintaining capacities and living fully is the primary goal, after all. Protect and optimize your body, all of us that is not the cancer. That sometimes gets lost in these decisions. Best wishes to you. Paul
Paul: Awesome post, love the metaphor! It is a given that we will underestimate both the wind and current and overestimate our craft. I’m over 70yr old, without diabetes, obesity or hypertension, I’ve blown away the median. Lol
Your insurance comment just introduced another variable that I didn’t know existed. This is the hardest job that I have ever had! Appreciated the Abi tip. I’ll run it by my MO
Judging by the user-I’d and metaphor, I’m sensing a Bay Area racer. In that case, it’s always the current.
Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy
After reading Getug-12 and 24 RTOG, I passed on D for stg-3b advanced PCa after HDR-BT/IMRT + ADT + AAP because I was G(3+4) and NM.
According to phase 2 trials in patients with no evidence of metastases but with PSA level progression (ie, increasing above a threshold defining the progression) after primary therapy, early docetaxel administration with or without ADT is feasible and active (ie, docetaxel exhibited efficacy).20-23 However, in a nonmetastatic rather than metastatic setting, the benefit of combining docetaxel with ADT did not prove to be as clear-cut in terms of overall survival (2% absolute benefit: HR, 0.87; P = .22) in a meta-analysis of phase 3 trials (GETUG-12,24 RTOG 0521,25 STAMPEDE,17 TAX 350126) even though failure rates were significantly reduced from 30% to 22% at 4 years (HR, 0.70; P < .001). To our knowledge, no predictive factors have been identified to help select patients who might benefit from initial therapy with ADT plus docetaxel vs ADT alone.
The present randomized clinical superiority trial compared ADT plus docetaxel with ADT alone in patients with localized PC treated by radical prostatectomy and/or radiotherapy who then developed rising PSA levels. The patients had no clinical or radiographic evidence of metastatic disease but presented high-risk factors. The primary outcome was PSA progression-free survival (PSA-PFS).
In your situation, what was the justification for recommending Docetaxel? Is it just an over abundance of caution? Does the PSMA capabilities eliminate the need to over treat?
It was Dr Scholz recommending D four years ago for locally advanced t3bN1M0+SV as complement to HDR/ADT/AAP. The European studies showed, lower-Gleason-nmHS subgroups did not benefit from adding D. As a G(3+4) and hyper-responder to ADT (PSA-u/d after HDR), I took the calculated risk to turn it down based on GETRUG-15.
My MO thinks for me ADT/Xtandi is better than starting docetaxel at this time due to low tumor burden. I am hoping to get into the PSMaddition trial. Hope to hear from the local hospital in the trial in gthe next couple days.
treedown: Very interesting trial. I’m curious as to your MO’s feedback about chemo vs the 2nd gen anti-androgen approach? Seems that you chose correctly.
I was curious and asked him directly, why he didn't even discuss it as listed in NCCN Guidlibe, and his response was that the side effects weren't worth the risk yet because I am hormone sensitive and only metastatic on PET. Right or wrong for me? I'll never know, but if I can get Pluvicto, considering where the PET scan found my mets on upper spine, I may be lucky. Ablative radiation was ruled as too risky to 1 or 2 of my 5 mets on PET. My RO looked really, really hard and couldn't find anymore so that's the encouraging part I will take from it because the rest was not encouraging at all.
Seems to me that with a psa at or about nadir then we can conclude that the PCa is relatively dormant - using ADT and Xtandi until something changes. Then chemo is reserved for when there are indications that PCa is growing again since it only works on fast dividing cells. Thats good enough for me (72yrs)
Early chemotherapy is the best. If you can go trough all 6 cycles. I did it 4.5 years ago and I am still only on ADT degarelix injection. Later I could start Enzalutamide and even later switch to olaparib + AAP.
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