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Recent clinical trial evidence has shown the benefit of triplet therapy -- androgen-deprivation therapy (ADT), docetaxel, and an androgen signaling inhibitor (ASI) -- in men with metastatic hormone-sensitive prostate cancer. But authors of a "Comments and Controversies" article in the asked whether docetaxel is truly needed, or whether ADT with an ASI might be the best option for most patients, sparing them toxicity.

No clinical trials have compared ADT plus an ASI head-to-head with ADT and docetaxel in these patients. However, recent subgroup and meta-analyses have provided some suggestive evidence, said Francisco Vera-Badillo, MD, of Queen's University in Kingston, Ontario, and Adi Kartolo, MD, of McMaster University in Hamilton, Ontario, who co-authored the article with Ian F. Tannock, MD, PhD, DSc, of Princess Margaret Cancer Centre of the University of Toronto.

In the following interview, Vera-Badillo and Kartolo elaborated on that evidence and discussed the implications.

What did the ARASENS and PEACE-1 clinical trials report about triplet therapy with ADT+docetaxel+ASI in men with metastatic hormone-sensitive prostate cancer?

In the phase III randomized trial, 1,306 men with metastatic hormone-sensitive prostate cancer (mHSPC) were randomized in a 1:1 ratio to receive darolutamide (ASI)+ADT+docetaxel or matching placebo+ADT+docetaxel (doublet therapy).

With a median follow-up of 43.7 months in the triplet therapy group and 42.4 months in the doublet therapy group, the authors found that risk of death was reduced by 32.5% in men with mHSPC who received triplet therapy compared with doublet therapy. Other clinically important secondary endpoints, such as time to pain progression and symptomatic skeletal event-free survival, also favored the triplet therapy group over the doublet therapy group, with an acceptable safety profile.

On the other hand, was also a phase III randomized trial with a 2×2 factorial design. It aimed to evaluate the role of additional abiraterone (androgen synthesis inhibitor; also designated as ASI), with or without radiotherapy, to standard of care (ADT alone).

Docetaxel was subsequently added to the standard of care as part of two major protocol amendments (optional in 2015, but then mandatory in 2017) to reflect the evolution of standard of care in men with mHSPC. The abiraterone groups were pooled together for survival analysis purposes, after determining that there was no significant interaction between abiraterone and radiotherapy.

With a median follow-up of 4.4 years for overall survival analysis, the authors found similar results to that presented in ARASENS, in which triplet therapy reduced risk of death by 25%, compared with doublet therapy, in men with mHSPC. Safety profiles were generally comparable, with slightly more grade ≥3 adverse events in the triplet therapy group (63%) than the doublet therapy group (52%).

What do you see as the major limitations of ARASENS and PEACE-1?

The major limitation of both trials was the lack of comparison of triplet therapy with another available doublet therapy option: ADT+an ASI. We knew from previous docetaxel trials (CHAARTED, GETUG-15, and STAMPEDE) that the survival benefits of additional docetaxel to ADT were apparent only in men with high-volume disease, defined by having visceral disease and/or having ≥4 bone metastases with ≥1 extra-axial metastases. In previous landmark studies involving an ASI, overall survival benefits of ADT+an ASI over ADT alone were generally observed across all subgroups of men with mHSPC, regardless of disease volume.

Additionally, the lack of direct comparison between triplet therapy and ADT+ASI also limited our interpretation of the safety profiles. While both triplet therapy and ADT+docetaxel groups had minimal grade 3-4 adverse events in the trials, most toxicities appeared to be docetaxel-related. It remains unclear if the added benefit of docetaxel outweighs its added toxicity.

There have been no head-to-head trials comparing ADT-ASI with ADT-docetaxel. But what have recent subgroup and meta-analyses found?

In the multi-arm, multi-stage STAMPEDE trial, ADT+an ASI was shown to have better failure-free survival but not overall survival, compared with ADT+docetaxel in men with both locally advanced and metastatic disease. A more recent network meta-analysis involving four contemporary phase III randomized trials (ENZAMET, ARCHES, TITAN, and PEACE-1) showed that overall survival was better in men with mHSPC receiving ADT+an ASI compared with ADT+docetaxel, and that triplet therapy was only favored over ADT+docetaxel but not ADT+an ASI in the survival analyses of men with mHSPC.

Lastly, subgroup analysis of PEACE-1 also suggested no significant overall survival benefit of triplet therapy over ADT+docetaxel in men with low-volume mHSPC. However, interpretation from these studies must be done with caution, given the limitation of indirect comparisons and inadequately powered subgroup analyses.

For which patients might therapy with ADT plus an ASI be most appropriate?

We believe ADT+an ASI may be appropriate in most cases of men with mHSPC, other than (1) asymptomatic men with HSPC of low-grade, low-volume, and slow disease progression from its initial local therapy, in which case ADT alone may be sufficient; or (2) men with HSPC of rapidly progressing, symptomatic, high-volume disease, in which docetaxel over ASI may be favored for a more rapid response. In the latter case, triplet therapy may be an option if there are no contraindication to either docetaxel or ASI.

Is there anything else you would like oncologists to understand about this issue?

Overall, we believed these were important studies which added more treatment options to our arsenals, but we need to remain cautious in terms of optimal patient selection. Although it was not discussed in our commentary, we must also consider the potential detrimental impact of triplet therapy on quality of life and financial toxicity.

At this time, use of triplet therapy may only be beneficial in limited circumstances such as in men with rapidly progressing, symptomatic, high-volume mHSPC who would otherwise be offered docetaxel. Otherwise, in the absence of head-to-head comparisons of triplet therapy versus ADT+an ASI, the default treatment option should be to a simpler, less toxic regimen.

Read the article here and expert commentary about it here.