Triplet therapy for newly diagnosed metastatic men beats docetaxel+ADT

(Updated)

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

The benefits of receiving the early triplet continued to be evident in patients who later received other therapies, demonstrating a benefit to the triplet over sequential therapy.

There was no increase in the incidence of severe adverse events from receiving docetaxel.

(Update 9/19/21) Karim Fizazi presented the following chart at the ESMO Congress today:

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). 

The full results will tell us how much the prostate radiation adds, and the effect on overall survival. The analysis by metastatic burden will be important too. Meanwhile, docetaxel+abiraterone+ADT should be considered the new standard of care.

How does this combination therapy compare to previous RCTs for docetaxel or abiraterone?

Because the STAMPEDE RCTs for docetaxel and abiraterone occurred at about the same time, 566 patients were randomized to one or the other. Sydes et al. reported the outcomes after a median of 4 years of follow-up. 

• 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

	abiraterone+docetaxel+ADT	docetaxel+ADT	abiraterone+ADT	ADT alone	Trial notes
PEACE1*	4.5 yrs	2.0 yrs			100% de novo, 100% perf. status 0, 57% high volume
STAMPEDE‡ (abiraterone)			Not reached (> 3.4 yrs)	2.0 yrs	94% de novo,26% perf.status 1 or 2, 55% high volume
LATITUDE* (abiraterone)			2.8 yrs	1.2 yrs	100% de novo, 45% perf. Status 1 or 2, 80% high volume/high risk
STAMPEDE‡ (docetaxel)		3.1 yrs		1.7 yrs	95% de novo, 56% high volume
CHAARTED§ (docetaxel)		2.8 yrs		1.7 yrs	73% de novo, 65% high volume

* time to radiographic progression or death

‡ time to first symptomatic event or death

§ time to symptoms or radiographic progression

While comparison is complicated, the extension of progression-free survival by 2.5 years by adding abiraterone to docetaxel alone is impressive. Docetaxel adds 1 - 1.5 years to progression-free survival over ADT alone. Abiraterone adds 1 - 1.5 years to progression-free survival over ADT alone.

II. Triplet Therapy with Nubeqa (darolutamide) - ARASENS

(Update 12/3/2021) Bayer announced that the combination of Nubeqa (darolutamide) and docetaxel + ADT increased survival over docetaxel + ADT alone in the ARASENS trial. This constitutes the second success for "triplet therapy."

(Update 2/15/2022) The first results of the ARASENS trial were presented at the 2022 ASCO Genitourinary Conference. All 1,306 patients treated from 2016-2018 were randomized to receive darolutamide (DARO) or placebo (PBO) on top of docetaxel and ADT. They found that:

• 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)

(update 8/5/22) The FDA has approved triplet therapy with Nubeqa (darolutamide) and docetaxel for men newly-diagnosed with metastases.

(update 2/18/23) Maha Hussain presented some planned subgroup results at the 2023 ASCO GU Conference. They defined two "volume groups" and two "risk groups" of the 1,305 men in the trial.

The volume groups were:

• 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

The risk groups were:

• 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

With about 4 years of follow-up:

• 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). The fact that the hazard ratios are similar suggests that the same benefit obtains regardless of volume and that only the immaturity of data is the reason for the lack of statistical significance.
• 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 (see this link) were similar in all subgroups.

(Update 4/21/24)The effect on PSA progression has been reported:

• The percent of patients with undetectable (<0.2) PSA at any time was higher with triplet - 67% vs 29%
• 62% vs 26% in the high-volume subgroup
• 84% vs 38% in the low-volume subgroup
• Time to PSA progression was 74% shorter without the triplet
• 70% shorter in the high-volume subgroup
• 91% shorter in the low-volume subgroup
• Undetectable PSA at 24 weeks predicted longer survival

III. SENESCENCE WITH SEQUENTIAL USE

Both the TITAN trial of Erleada (apalutamide) and the ENZAMET trial of Xtandi (enzalutamide) showed no benefit for the advanced hormone therapy when docetaxel had been used previously. Timing is important! When chemo or advanced hormone therapy is used as monotherapy, protective mechanisms (like cellular senescence) kick in soon afterward. It protects the cancer cells from destruction by the other medicine. They have to be used together or wait until the first drug stops working.

IV. (Update 6/6/22) Triplet Therapy with Xtandi (enzalutamide)

An updated, subgroup analysis of the ENZAMET trial among newly diagnosed men with metastases confirms the triplet of ADT+enzalutamide+docetaxel increases survival. 5 year survival was 60% for the triplet vs 52% for ADT+docetaxel. The benefit was especially pronounced in the first 2 years of triplet therapy in men with high volume metastases. There was no benefit to the triplet in recurrent men with metachronous metastases.

V. Does docetaxel only benefit mHSPC patients with a high-volume of metastases?

This has stirred much controversy. Gravis et al. argue that the overall survival improvement from docetaxel was seen in CHAARTED only among men with high-volume metastases was a real biological effect (i.e., that high-volume PC is a different disease from low-volume PC, that responds differently to chemo). Armstrong argues for a biological difference. They acknowledge, however, that the small sample size of de novo men with low volume metastases (n=154) and their short follow-up (only 16% had died during the 48 months of follow-up) may be underestimating the benefit in the low volume, de novo subgroup. Remember that in CHAARTED, the low-volume subgroup was not recruited initially, so the follow-up is shorter in the group that needs the longer follow-up.

Clarke et al. argue that STAMPEDE is the more definitive trial because its sample size of mHSPC men with low-volume metastases was over twice as great (n=362) and the follow-up was longer (62% of the docetaxel patients had died during 78 months of follow-up). They did not find evidence of heterogeneity - low-volume PC responded just as much to chemo as high-volume PC. While the effect on low volume PC was similar, the statistical confidence in its effect did not meet 95% confidence. They attribute this to insufficient sample size (power). Suzman and Antonarakis agree that chemo should be offered to all mHSPC men, regardless of volume of metastases. It would seem that a meta-analysis combining the low-volume, de novo subgroups from both CHAARTED and STAMPEDE might be sufficiently powered to provide a more definitive answer. Patients wishing to understand why analyses of subgroups are controversial, may be amused by this analysis of STAMPEDE subgroups. The authors found that patients born on a Monday benefited the most from abiraterone, and it was statistically significant. while patients born on a Friday had the least benefit, and it wasn't statistically significant. They further found that men diagnosed on a Monday did not benefit from abiraterone, whereas men diagnosed on other days had a statistically significant benefit. These absurd findings are sometimes known as "p-hacking" or "data dredging." This interview discusses this error and the mistake of drawing biological inferences from statistical significance. Pre-specifying subgroups is one way to avoid such errors, but drawing conclusions from inadequately powered subgroups, while tempting, should be avoided. This controversy is reflected in the conflicting recommendations that constitute the standard of care.

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 [1070]"

I personally believe that the STAMPEDE researchers make a stronger case pending better data from PEACE1.

It is also possible that genomics will allow better selection of patients for early chemotherapy. Hamid et al. examined tissue collected for the CHAARTED trial. They found a subtype called "Luminal B" that was associated with improved survival from chemotherapy. This finding has not yet been validated on an independent trial. Meanwhile, DECIPHER provides the test as part of its GRID analysis.

The major advantages of early chemo vs "saving it for later" are:

• 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