I. Triplet therapy with abiraterone (PEACE1)
(Update 4/9/22) Fizazi et al. published the full results of PEACE1 in The Lancet. PEACE1 was a European randomized clinical trial (RCT) conducted from 2013-2018 among 1,173 men who were newly diagnosed with metastases. All patients got standard of care, which consisted of ADT and docetaxel (after 2015).
They randomized patients to get:
- prostate radiation or not
- abiraterone+prednisone or not
After median follow-up of about 3-4 years, they found that prostate radiation:
- prostate radiation reduced mortality by about a quarter in men who got docetaxel, but it was not statistically significant.
- prostate radiation cut radiographic progression-free mortality in half.
Adding abiraterone to standard of care (including docetaxel):
- Increased median survival from 4.4 years to >5.7 years (not reached)
- Mortality was cut by 25%
- Cut by 28% in those with high volume metastases
- Cut by 17% in those with low volume metastases (not statistically significant)
- Increased radiographic progression-free survival from 2.0 years to 4.5 years
- Radiographic progression was cut in half
- Radiographic progression was cut by 53% in those with high volume metastases.
- Radiographic progression was cut by 42% in those with low volume metastases.
- Time to castration resistance increased from 1.4 to 3.2 years
- Castration resistance was cut by 62%
- Prostate cancer-specific survival increased from 4.7 years to not reached, a 31% decline in prostate cancer mortality
There was no increase in the incidence of severe adverse events from receiving docetaxel.
Combining docetaxel and abiraterone in men who were originally diagnosed with high volume metastases increased overall survival significantly over either alone.
(May 23, 2021) The first results of the long-awaited PEACE-1 randomized clinical trial (RCT) are in. They randomized newly diagnosed metastatic men to either prostate radiation or abiraterone or standard-of-care (SOC). SOC included docetaxel for many of the men.Radiographic progression-free survival increased by 2.5 years (from 2.0 to 4.5 yrs) with the addition of abiraterone to docetaxel. Time to castration resistance increased by 1.7 yrs (from 1.5 to 3.2 yrs).
- Abiraterone reduced PSA more quickly, as reflected in "failure-free survival" (time to PSA increase, clinical progression, or death) and "progression-free survival" (time to first "failure" event, excluding PSA).
- Those who received docetaxel first soon caught up. There were no significant differences in "metastasis-free survival," "prostate cancer-specific survival," "overall survival," or "time to the first skeletal-related event (pain or fracture)"
- Serious toxicity (Grade 3 or greater) was also equal: 50% for docetaxel, 48% for abiraterone.
The STAMPEDE researchers (the STOPCAP group) did a meta-analysis of the STAMPEDE trials that concluded that abiraterone probably had a greater effect than docetaxel, but unlike the analysis above, it was not a direct comparison. They concluded that either should be recommended.
The other RCTs for metastatic hormone-sensitive prostate cancer (mHSPC) included STAMPEDE- abiraterone, LATITUDE- abiraterone, STAMPEDE-docetaxel, CHAARTED-docetaxel.GETUG-AFU-15(docetaxel) did not detect a difference in survival from the early use of docetaxel. 30% had prior treatment. There were differences in the populations studied in each trial that should be understood.
LATITUDE screened for more advanced patients - 80% were "high risk." High risk was defined by having 2 of 3 "high-risk" features, either: Gleason 8-10, or ≥ 3 bone metastases or visceral metastases. About half had performance status of 1 or 2 ("0" is the best performance status).
CHAARTED started by recruiting only patients with a high burden of metastases. But only 73% were de novo, meaning 27% had been previously treated before they entered the trial. They later opened the trial to men with fewer metastases and ended up with a small group (27%) of low burden de novo patients. They defined "high burden" as visceral metastases or ≥ 4 metastases with at least 1 outside the axial skeleton.
The two STAMPEDE trials recruited almost entirely (95%) de novo patients. 56% were "high burden" by the CHAARTED definition. 52% were "high risk" by the LATITUDE definition. 26% had performance status of 1 or 2.
PEACE1 recruited only de novo metastatic patients, with excellent performance status. 57% had high-risk features by the LATITUDE definition.
The following chart shows how long it took for patients to progress on each of the early interventions. Complicating analysis, each trial used a slightly different definition of progression.
Time to "progression" following each early therapy
- DARO significantly decreased the risk of death by 32.5%
- The survival advantage subsisted even though the PBO group received more therapies later
- The survival advantage was maintained in all subgroups (i.e., disease extent, type of metastases, ALP levels)
- DARO delayed time to castration resistance by 64%
- DARO delayed time to pain progression by 21%
- DARO delayed time to first skeletal event/fracture
- DARO delayed time to next chemotherapy
- Treatment-related adverse events were similar and were highest during the time chemo was given (mainly neutropenia)
- Treatment discontinuation was low and similar in both groups (13.6% for DARO) vs (10.6% for PBO)
- High Volume (77% of patients)= Visceral metastases and/or 4 bone metastases with at least one outside of the axial skeleton
- Low Volume (23% of patients) = Every other newly-diagnosed metastatic man in the trial
- High Risk (70% of patients) = any ≥2 of these risk factors: Gleason score≥8, ≥ 3 bone metastases, visceral metastases.
- Low Risk (30% of patients) = Every other newly-diagnosed metastatic man in the trial
- Overall survival increased significantly in the High Volume (mortality risk reduced by 31%). In the Low Volume subgroup, the difference (by 32%) was not yet statistically significant, but may be with larger sample size or more time (survival curves separated after 3 years).
- In High Risk (mortality risk reduced by 29%), and Low Risk (by 38%) subgroups, the differences were statistically significant.
- Time to castration resistance increased significantly in all subgroups.
- Time to next chemotherapy increased significantly in all subgroups.
- Adverse events were similar in all subgroups.
The current NCCN guidelines state: "Docetaxel should not be offered to men with low volume metastatic prostate cancer, since this subgroup was not shown to have improved survival in either the ECOG study or a similar European (GETUG-AFU 15) trial." The current ASCO guidelines state: "Recommendation 1.2. For patients with low-volume metastatic disease (LVD) as defined per CHAARTED who are candidates for chemotherapy, docetaxel plus ADT should not be offered (Type: evidence-based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong for patients with LVD)." On the other hand, the current AUA/ASTRO/SUO guidelines state: "15. In patients with mHSPC, clinicians should offer continued ADT in combination with either androgen pathway directed therapy (abiraterone acetate plus prednisone, apalutamide, enzalutamide) or chemotherapy (docetaxel). (Strong Recommendation; Evidence Level: Grade A) Canadian Urological Assn (CUA) guidelines state: "Docetaxel plus ADT may also be an option in patients with mCNPC/mCSPC with good performance status with low-volume disease (Level 2, Weak recommendation)." NICE (UK) guidelines state: "Offer docetaxel chemotherapy to people with newly-diagnosed metastatic prostate cancer who do not have significant comorbidities." European Urological Assn (EAU) guidelines state: "Based on these data, upfront docetaxel combined with ADT should be considered as a standard in men presenting with metastases at first presentation provided they are fit enough to receive the drug "
- Longer survival advantage
- Side effects are milder when patients are less debilitated from years of cancer
- As many as 10 infusions (usually 6) can be given if it is well tolerated
- Most patients are not resistant, so docetaxel can be repeated
- If there is resistance, cabazitaxel can be given