The so-called PEACE-1 trial is an ongoing Phase III trial among men diagnosed with de novo metastatic castration-sensitive prostate cancer (mCSPC). The earliest results of this trial are to be presented by Fizazi et al. at the upcoming annual meeting of the American Society for Clinical Oncology (ASCO).
The PEACE-1 trial is a complex four-arm trial, and there were added complexities during the course of the trial that we will try to explain below. Patients with newly diagnosed, mCSPC were randomly assigned to one of four arms of the trial as follows:
- Normal “standard of care” or SOC
- Normal SOC + abiraterone acetate + prednisone
- Normal SOC + radiotherapy
- Normal SOC + abiraterone acetate + prednisone + radiotherapy
However, initially, the “normal” SOC was androgen deprivation therapy (ADT) alone. Then, after October 2015, the “normal” SOC was changed to ADT + docetaxel chemotherapy at the investigator’s discretion (because of the results of other trials like the CHAARTED trials). Then after publication of the data from the STAMPEDE and the LATITUDE trials in 2017. accrual of patients was limited to men who were already previously treated with ADT + docetaxel.
Now we would point out with care that these changes in the trial protocol were almost certainly appropriate and necessary. However, they do complicate the interpretation of the preliminary results of the PEACE-1 trial (at least in our opinion).
The trial has two co-primary endpoints: radiographic progression-free survival (rPFS) and overall survival (OS).
Over the 61 months of accrual of patients to this trial — from November 2013 to December 2018:
- 1,173 men were enrolled in total.
- SOC was ADT alone in 463 patients.
- Revised SOC was ADT + docetaxel in 710 patients.
- Median age was 67 years (IQR: 60-72).
- 57 percent of patients had “high-volume” metastases.
- 43 percent of patients had “low-volume” metastases.
- Median follow-up is 3.5 years as of the current report.
Fizaz et al, in the abstract of their paper to be presented at ASCO, state very clearly, that
The required number of rPFS events to achieve 80% power has been reached for the abiraterone question (not yet for the RXT question).
They go on to justify their interpretation of the results from the rPFS data, which they report as follows:
- rPFS was significantly improved in
- The abiraterone arm in the overall population (hazard ratio [HR] = 0.54; medians: 2.2 vs 4.5 years)
- The ADT + docetaxel population (HR = 0.50; medians: 2.0 vs 4.5 years)
- bPFS (PFS including PSA progression as an event) was also significantly improved in
- The abiraterone arm in the overall population (HR = 0.40 ; medians: 1.5 vs 3.8 years)
- The ADT + docetaxel population (HR = 0.38; medians: 1.5 vs 3.2 years).
They go on to report that
- Grade 3/4 adverse events were observed in > 5 percent of patients within the first 6 months in the ADT + docetaxel population and in the abiraterone and control arms, respectively.
And they conclude that
Adding abiraterone to ADT + docetaxel significantly improves rPFS in men with de novo metastatic prostate cancer, with about 2.5 years of absolute benefit in medians, and no meaningful additional short-term toxicity.
However, there is another way to look at all these data. That is that, at the end of the day, there were really 12 different arms to this trial (three versions each of the four arms listed above). And consequently we are of the opinion that the data from each of these 12 sets of patients should be analyzed separately.
It may well be that this would not make a meaningful difference to the results of the PEACE-1 trial, but — at this time — we do not believe that these data justify the decision that ADT + docetaxel + abiraterone acetate + predisone is now the SOC for the first-line treatment of men with newly diagnosed metastatic castration-sensitive prostate cancer (de novo mCSPC). On the other hand, we do believe that this is a reasonable course of therapy today for carefully selected patients at the clinician’s discretion, and depending on the precise diagnostic status of the patient at time of initiation of such treatment — with or without radiotherapy (which certainly still remains an option at the clinician’s and patient’s shared discretion).
The final overall survival data may well also have significant impact on the assessment of any new SOC for the initial treatment of de novo mCSPC. However, it is unclear whether we will know anything more about the appropriate type of radiotherapy (prostate alone; prostate + pelvic; or prostate _+ pelvic + oligometastatic disease). Appropriate selection of the right patient for any one of several tryes of therapy under thee circumstances is going to remain complicated for some time — in our opinion.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: castration-sensitive, de nove, earky, mCSPC, metastatic, PEACE-1, results, rPFS, trial |
THE "NEW" PROSTATE CANCER INFOLINK 
I certainly look forward to the peer-reviewed published results, and the additional details as the various survival landmarks are reached.
IMO this was one of the best RCTs on de novo mHSPC therapy. Their 2×2 factorial design will allow for four different well-powered analyses. (I didn’t understand how you came up with 12). There will be certain subgroup analyses, such as metastatic burden, that will be interesting certainly. But to be practice-changing, the group getting the therapy has to be: (1) sufficiently powered and (2) statistically better than the control.
PEACE-1 has met both of these criteria for Zytiga + docetaxel. The median time to radiographic progression of 4.5 years (vs 2.0 years for docetaxel) is frankly, more than I would have imagined. We know from a randomized arm of the STAMPEDE trial that docetaxel and Zytiga afford equivalent survival benefits. They each add 1.1 to1.6 years to radiographic or symptomatic progression-free survival over ADT alone in the four RCTs so far, and the magnitude of benefit is well beyond what has been seen with sequential use.
Docetaxel and abiraterone kill prostate cancer with two entirely different mechanisms. Abiraterone inhibits the androgen receptor, while docetaxel stabilizes microtubules. It’s been found that doubling up on AR-directed therapies (at least with Zytiga and Xtandi) or using them sequentially has little extra value. Attacking on these two different fronts seems to be synergistic.
Thank you Sitemaster for this very interesting and valuable reporting.
As a layman trying to think like an oncologist here, I’m suspecting there is now enough evidence, from this trial and other studies, particularly CHAARTED, to use the Standard-of-Care (SOC) plus abiraterone acetate with prednisone (Zytiga plus prednisone) plus early docetaxel in men with a HIGH BURDEN of metastases. (“High burden”: 4 or more bone metastases with at least one lesion outside the axial skeleton and/or visceral metastases.)
This relates to the following part of your report, which focuses on ALL men with newly diagnosed metastatic prostate cancer: “It may well be that this would not make a meaningful difference to the results of the PEACE-1 trial, but — at this time — we do not believe that these data justify the decision that ADT + docetaxel + abiraterone acetate + predisone is now the SOC for the first-line treatment of men with newly diagnosed metastatic castration-sensitive prostate cancer (de novo mCSPC). On the other hand, we do believe that this is a reasonable course of therapy today for carefully selected patients at the clinician’s discretion, and depending on the precise diagnostic status of the patient at time of initiation of such treatment — with or without radiotherapy (which certainly still remains an option at the clinician’s and patient’s shared discretion).”
I’m thinking that using the combo in men with a HIGH BURDEN OF METASTASES at diagnosis is what you were getting at in the last sentence. Other trials have indicated that there may be no benefit from early docetaxel for men with a LOW BURDEN of metastases at diagnosis. Based on what is known at this time, if I were a patient newly diagnosed with a high burden of metastases, I would be eager to get the combined treatment, but not interested in the combination if I had a low burden of metastases. I realize that these issues are not settled yet, but it seems there is enough information to make decisions based on odds with a good measure of confidence.
How would you feel if you were one of these newly diagnosed patients? (And I am grateful that neither of us is actually faced with that choice.)
Dear Jim:
I was actually being very careful to avoid any specific set of distinctions regarding disease burden or any other factors. Just as one example, the currently available report from the PEACE-1 trial doesn’t tell us anything about tumor aggressiveness. I might have a different attitude if I was a patient who had Grade Group 5 disease as opposed to Grade Group 3 disease — even if it was low tumor burden. My point was only that each individual patient needs to be carefully assessed as to the appropriateness of his de novo mCSPC before any decision is made about his treatment.
Jim:
I agree with the Sitemaster that there is no info yet on disease burden. The trial was powered to be definitive on the total, regardless of disease burden subgroups. Disease burden with chemo is a thorny issue and many smart people come down on different sides. As a research/statistics stickler, I agree with the Canadian Urological Association (CUA), the European Urological Associatin (EAU), NICE (UK), and AUA/ASTRO/SUO in their recommendation to offer chemo to all de novo metastatic patients regardless of disease burden who can tolerate it. I think that NCCN and ASCO erred in their guidelines. I am prepared to change my mind if someone does a meta-analysis among both STAMPEDE and CHAARTED (and PEACE-1) de novo patients, or if there is a sufficiently powered new RCT (unlikely).
Sitemaster and Allen,
Thank you both for your thoughtful replies.
I too respect the need for sound statistical data and try not to drive ahead of the headlights. I have not yet checked the various guideline groups; thanks for pointing out their stances.
I applaud the efforts of the PEACE-1 investigators to arrive at some conclusions, but unfortunately their message is somewhat garbled given the sequential changes … unless of course we take STAMPEDE results at face value (per OS results) even though metastatic prostate cancer was not differentiated (very small numbers). However, the difference in STAMPEDE between OS with AAP vs. ADT alone is rather small (86% vs. 77%). For me, STAMPEDE was a different situation entirely than PEACE-1.
Adverse events with docetaxel were not extreme here in PEACE-1, but not to be dismissed as irrelevant in terms of quality of life (about 35%).
Overall, with some assumptions, ADT+ docetaxel + abiraterone improvement in OS was truly significant versus ADT monotherapy.
Sharon:
STAMPEDE certainly had very large numbers (n = 1002) of de novo metastatic patients. That was its main purpose. Among metastatic patients in STAMPEDE, the hazard ratio in OS between those that received AAP + ADT vs ADT alone was 0.60 (a 40% improvement in survival). You are only looking at 3-year OS rates, which are very high irrespective of which treatment they got. The 5-year OS rates were 60% for AAP + ADT but 40% for ADT alone.
In PEACE1, 60% of the patients men got ADT+docetaxel (n = 710) and about 40% got ADT-alone (n = 463) as their standard of care. They were then randomized to receive abiraterone or not. That was because “standard of care” changed while they were recruiting, and it would have been unethical to deprive them of a therapy that had already been proven to extend life. This combined “standard of care” is what is called the “overall population” in the article above, but they also included the comparison with the ADT + docetaxel group. They have not yet reported the “ADT-alone” group.
More recently, they reported OS rates for patients with high metastatic burden. Median survival was 61 months if they received the “triplet” but only 42 months if they received ADT + docetaxel. Bayer reported that another triplet therapy – ADT + docetaxel + darolutamide – increased survival over ADT+docetaxel in the ARASENS trial. Data will be revealed at an upcoming conference.