So the data from the CHAARTED trial will be presented this afternoon at the ASCO meeting. This is the one really major and positive study result related to prostate cancer that we knew was coming at this meeting.
Sweeney et al. (see abstract no. LBA2) set out to evaluate whether there was a benefit to up-front chemohormonal therapy for men with newly diagnosed, metastatic prostate cancer, as compared to just androgen deprivation therapy (ADT) alone.
They randomized eligible patients to treatment with either ADT alone or ADT + docetaxel (at a dose of 75 mg/m2 every 3 weeks for 6 cycles) without prednisone within 4 months of starting ADT. They also stratified the patients in a number of ways, e.g.,
- Men with high volume disease (i.e., visceral metastasis and/or four or more bone metastases) vs. low volume disease
- Anti-androgen use for > 30 days or ≤ 30 days
- Age ≥ 70 or < 70 years
To be eligible for enrollment in the trial, the patients had to have organ and neurological function appropriate for treatment with docetaxel; they could have had no more than 2 years of adjuvant ADT; and they could have had no disease progression within 12 months of any adjuvant ADT. The primary study endpoint was overall survival.
Here are the core study results (some of which have been reported previously in a media release in late 2013). However, the data reported here reflect a more recent analysis dated January 16, 2014:
- 790 patients were enrolled in the trial between July 2006 and November 2012.
- 393 men were randomized to ADT alone.
- 397 men were randomized to ADT + docetaxel
- The average (median) age of the patients was 63 years (range, 36 to 91 years)
- The vast majority of the patients
- Had a “good” ECOG performance status of 0 or 1 (98 percent)
- Were Caucasians (89 percent).
- 24 percent of patients had had prior radiotherapy.
- 24 percent of patients had had a prior radical prostatectomy.
- 64 percent of patients on ADT alone had high volume metastatic disease.
- 67 percent of patients on ADT + docetaxel had high volume metastatic disease.
- Median follow-up was 29 months, at which time
- 137 deaths had occurred among men on ADT alone
- 104 deaths had occurred among men on ADT + docetaxel
- Median overall survival data showed the following:
- For all 790 patients in the trial
- 42.3 months for men on ADT alone
- 52.7 months for men on ADT + docetaxel
- These data are statistically significant (hazard ratio [HR] = 0.63; P = 0.0006).
- For the 520 patients with high volume, metastatic disease
- 32.2 months for men on ADT alone
- 49.2 months for men on ADT + docetaxel
- These data are statistically significant (HR = 0.62; P = 0.0012).
- Median survival for men with low volume, metastatic disease had not been reached.
- For all 790 patients in the trial
- About 28 percent of patients treated with ADT + docetaxel exhibited serious (Grade 3 or 4) adverse effects.
- 1 patient treated with ADT + docetaxel died due to his treatment.
Sweeney et al. conclude that combination chemohormonal therapy with ADT + docetaxel + prednisone improves overall survival compared to ADT alone in men with newly diagnosed, high volume, metastatic prostate cancer. They note that longer follow-up is needed to see if a survival benefit can be demonstrate for newly diagnosed men with low-volume, metastatic disease.
It should be noted that there seemed to be some relatively small differences between the information provided in the late-breaking abstract of this paper and the actual data reported by Dr. Sweeney. It will therefore be important to double-check these data when the final paper is published.
As we have mentioned previously, at least for those men with high volume, metastatic disease at the time of diagnosis, this study clearly “changes the game” with respect to the treatment of their metastatic disease since combination chemohormonal therapy appears, on average, to extend their overall survival for at least a year compared to ADT alone. It will also affect the potential use of drugs like abiraterone acetate and enzalutamide in such patients (at least until we have learned more about the potential uses of such drugs in the early stages of metastatic prostate cancer).
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: androgen deprivation, chemohormonal, docetaxel, metastatic |
THE "NEW" PROSTATE CANCER INFOLINK 
Any thoughts on why docetaxel worked so well in this prostate cancer trial, but in previous trials showed only minimal positive effects?
Did the docetaxel work because the patients were not hormone resistant by the time they got the docetaxel, or because of the type of ADT they were receiving this time around?
Many prostate cancer patients in the past have elected to pass on docetaxel chemotherapy because it only offered 3-4 months of added life, which was not enough benefit for them considering how sick the chemo would make them. This impression was confirmed by previously published docetaxel trials.
Thank you for your thoughts on this.
Dear Walter:
The type of ADT being used was certainly not the issue. It appears to be clear that the difference was that the patients in this trial were not castration resistant, and were much earlier in the process of management of metastatic disease. I would emphasize, however, something that many in the medical oncology community are emphasizing: the available data show a very clear survival benefit for the patients with a high metastatic impact (either visceral disease or 4+ bone metastases in this study); the potential for benefit in men with bone-only, lower-volume metastatic disease is unproven at this time.
Sitemaster,
Thank you for your reply.
Yes, this trial does represent a major breakthrough in prostate cancer treatment.
In trying to understand why docetaxel worked better this time around, could the dosage and the dosing schedule been a factor, as possibly suggested by the seemingly high frequency of side effects?
The same question was posed to Dr. Sweeney by email yesterday . If he replies, his answer will be posted here as well.
Walter:
The dose and dosing schedules of docetaxel were standard ones — although only six cycles of chemotherapy were administered. Interestingly, however, patients were not required to take prednisone along with the docetaxel. This may have had some impact.
The data reported is extremely confusing to me.
(1) Almost one half of the patients had had RP or RT, but apparently they are lumped together with those who never had any definitive treatment, so there is no way to know if longer survival was more related to initial definitive therapy than ADT + docetaxel.
(2) A patient was eligible to participate in the study, but it was OK for these “newly diagnosed” patients to have had up to 24 months of previous ADT.
(3) 64% of patients were on ADT alone and 67% were on ADT + docetaxel, a total of greater than 100% of patients with high volume metastatic disease.
(4) The median survival of all patients was reported, but at the same time, median survival of low volume disease patients had not yet been reached.
I followed the link to the abstract, but it was not helpful. Am I completely misunderstanding the statistics?
Thank you.
Richard
Dr. Sweeney e-mailed me back to my question about why he thought the docetaxel worked in his trial — “We had a lot of patients with high volume disease” is what he said.
That was very nice of him to get back to me.
I am not sure I understand the mechanism(s) involved in its success, but will wait for further comments on the trial.
My mother-in-law developed Stage III breast cancer a few years ago. She was estrogen positive. She did chemo, radiation, and hormone therapy (whatever the drug is to block estrogen) “continuously” for 5 years.
Aren’t we just learning what the breast cancer studies have shown for years — that chemotherapy given early and hormone therapy given continuously is best for overall survival?
I realize we all want to avoid chemotherapy, but numbers like this make us all think. I’m on intermittent hormone therapy and have bone mets and wonder if I should do this combo when the vacation is over. … I thought I threw the kitchen sink at it before, but I’m left thinking there was more sink to throw. If the difference seems to be hormone sensitivity, if we are at extremely high risk, … why wouldn’t we consider adding this?
Is there any information on Gleason scores/PSA levels of these patients?
Was it just Lupron that was used for hormone therapy?
Are there similar studies going on with early chemo and hormone therapy that may be interesting and ending soon?
Thanks …
Dear Richard:
You appear to be misunderstanding the data.
Re: item (1) above … Survival times in this trial were only being measured from time of treatment for metastatic disease. Thus, a patient may or may not have already benefited from prior first- and second-line therapies. That is not a factor in this study. For example, the study might have included some patients who had metastatic disease at initial diagnosis with prostate cancer and some patients who were initially diagnosed with apparently localized Gleason 8 disease, treated surgically, progressed 3 years later, treated with salvage radiation therapy + 6 months of adjuvant ADT, and then become metastatic (say) 4 years later. According to Dr. Sweeney in giving his presentation, the effects of therapy on the men with high volume metastatic disease when they were entered into the trial appear to have been valid regardless of such prior treatment issues.
Re: item (2) above … Patients were eligible for this trial when they were first identified as having metastatic disease, largely regardless of when they became metastatic and what treatments they may or may not have had before. They were also eligible if they had had previously had < 24 months of adjuvant ADT (e.g., radiation therapy + ADT) and had progressed within 12 months of having such adjuvant ADT. However, they were not eligible for the trial if they had had primary ADT as therapy before becoming metastatic or if they had had > 24 months of adjuvant ADT or if they had progressed to having metastasis within 12 months of having adjuvant ADT.
Re: item (3) above … There were 790 patients in the trial, of whom 393 (49.7%) were given ADT alone and 397 (50.3%) were given ADT + docetaxel. Of the 393 patients on ADT alone, 64% (i.e., 252) had high volume metastatic disease; of the 397 patients on ADT + docetaxel, 67% (i.e., 266) had high volume metastatic disease.
Re: item (4) above … The median survival of all patients in the trial had been reached at the time of data evaluation; so had the median survival of all the patients with high volume metastasis. However, the median survival of the relatively small number of patients in the trial with low volume metastasis had not been reached at the time of data evaluation. Thus, one can evaluate the impact of therapy on all the patients, and on all the patients with high volume disease, and it is clear that the effect on all of the patients is predominantly a consequence of the effects of therapy on the patients with high volume disease because there was not — at the time of evaluation — any significant effect on the patients with low volume disease.
I hope this helps.
Walter:
It is important to understand that three key factors in this trial were: (a) that the patients had not (generally) had long periods on ADT prior to enrollment in this trial, and so they were probably relatively healthier than the men treated with chemotherapy in most prior trials; (b) that the patients were not castration-resistant at the time of treatment; and (c) that the patients in whom the combination of ADT + docetaxel seems to have worked (to date) seems to have been only the men with high volume disease (most of the men in the trial, as Dr. Sweeney noted in his e-mail to you).
In addition, as I pointed out before, the fact that no prednisone was being given to patients in this trial may also have been a significant factor.
Dear Jerry:
I want to emphasize, as did Dr. Sweeney and others who have already commented in professional forums, that the CHAARTED study has shown a significant benefit exclusively in the patients who had evident high volume metastasis. No study to date has ever shown a similar effect in patients with low volume metastasis. There are lots of other studies going on now, but it wouldn’t be wise to try to prejudge their results.
I would also want to emphasize that, just as we are beginning to understand that there has been vast over-treatment of prostate cancer (even though some of us had argued this for years), there has also been vast over-treatment of breast cancer. That isn’t meant to imply that you mother-in-law was inappropriately treated. On the other hand, as with prostate cancer, it is becoming clear that lots of women with breast cancer get very aggressive forms of treatment that are not necessarily justified by their clinical status because they might well respond just as well later on if their disease was to progress.
I am sure there will be a lot of detail about things like Gleason scores and PSA levels in the full data from the CHAARTED trial when it gets published. Dr. Sweeney had 12 minutes to present a complex paper. However, he was very clear that there were no obvious discriminators indicating that a patients prior Gleason score of PSA level or other factors were affecting the results.
There are indeed other studies going on in men with low volume metastasis and in high-risk men with no visible metastasis. Exactly when these are going to report results is unknown at this time (but I am expecting at least one of them to report at ASCO next year).
Thanks Sitemaster for clearing up the statistics. I would have been totally lost on this one without your explanation.
Richard
Sitemaster: Is one of the studies to be presented in 2015 addressing high-risk men with no visible metastases? Thanks.
Dear Dan:
I hope that there may be at least a couple of studies reported in 2015 that address the potential treatment of this group of patients. I am aware of several ongoing studies in (or specifically including) this subset of patients that might report out in the next 18 months.
Is the article already published? If it is, where can I get it?
Claire:
No. This article has not yet been published. The paper was presented at ASCO and you can download the abstract from that meeting, but that’s it.
I am actually grateful to the holder of this site who has shared this wonderful article at at this time.