APCCC 2021: What Is the Evidence for “Triplet Therapy”?

(UroToday.com) The Advanced Prostate Cancer Consensus Conference 2021 meeting session discussing the management of newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) included a presentation by Dr. Ian Davis regarding the evidence for “triplet therapy”, specifically ADT + docetaxel + primary additional systemic therapy.

Dr. Davis started by highlighting a summary table of trials assessing ADT + two other agents:

APCCC Ian Davis-0.jpg 

The TITAN trial,1 assessed ADT + apalutamide versus placebo among 1,052 men with mHSPC, including 63% of men with high-risk disease and 81% with synchronous M1 disease. Additionally, 11% of patients in TITAN who received docetaxel, which was a stratification factor in the trial, was completed before the commencement of apalutamide, was excluded if there was progressive disease before receipt of docetaxel, and was delivered with a median of six cycles. Among patients with prior docetaxel use, there was no benefit to receipt of apalutamide on overall survival (HR 1.12, 95% CI 0.59-2.12), however, there was a benefit for apalutamide noted for patients without receipt of docetaxel (HR 0.61, 95% CI 0.50-0.76). Dr. Davis highlighted that there was no specific safety information reported for the docetaxel cohort of patients.

In the ARCHES trial,2 1,150 patients with mHSPC were randomized to ADT + enzalutamide versus placebo, including 63% with high-risk disease and 67% of patients with synchronous M1 disease. In ARCHES, 18% of patients who received docetaxel, which was also used as a stratification factor, was completed before enzalutamide was commenced, was excluded if there was progressive disease before receipt of docetaxel, and included 90% of patients receiving six cycles of therapy. Among patients with a prior history of docetaxel, enzalutamide improved progression-free survival (HR 0.52, 95% CI 0.30-0.89), which was also consistent among men with no prior docetaxel therapy (HR 0.37, 95% CI 0.28-0.49). With regards to overall survival (OS), among patients previously treated with docetaxel, there was no survival benefit with the addition of enzalutamide (HR 0.74, 95% CI 0.46-1.20), whereas there was a survival benefit among patients with no prior docetaxel (HR 0.64, 95% CI 0.51-0.81). Similar to the TITAN trial, there was no specific safety information for the docetaxel cohort.

In the ENZAMET trial,3 1,125 men were randomized to enzalutamide + ADT versus active control. This included 53% of men with high-volume disease and 45% receiving concurrent docetaxel. Among those receiving docetaxel, 61% of patients were high-volume and 27% were low volume; 76% of patients randomized to enzalutamide received six cycles of docetaxel compared to 65% of patients in the control arm. Since this was an open-label study, there was safety data available, including an apparent increase in docetaxel toxicity with enzalutamide. Based on the interim analysis that has been reported to date, there is no OS benefit with triplet therapy (HR 0.90, 95% CI 0.62-1.31), however, there is a strong progression-free survival (PFS) signal as a secondary endpoint (HR 0.48, 95% CI 0.37-0.62):

APCCC Ian Davis-1.jpg 

Turning to the PEACE-1 trial, Dr. Davis notes that patients were randomized to abiraterone versus placebo, of which 57% had high-burden disease, including 64% high-risk patients in the docetaxel-treated group. Concurrent docetaxel was received by 60% of patients; initially ADT alone (n=273), then permitted (n=592), then mandatory (n=308). Docetaxel was used as a stratification factor, was excluded if there was progressive disease before receipt of docetaxel, and included 90% of patients receiving six cycles of therapy. PEACE-1 showed a benefit for abiraterone and for abiraterone + docetaxel, with an rPFS benefit in high and low volume disease, and with an OS benefit evident in high-volume disease however with immature data for the low volume group. Dr. Davis highlighted that docetaxel safety does appear similar with or without abiraterone therapy.

Presented at ESMO 2021, the STAMPEDE trial assessed abiraterone with or without enzalutamide added to ADT compared to ADT alone for 1,974 men with high-risk non-metastatic prostate cancer. All of these patients were M0, however, 39% were N1 and 3% had relapsed after prior therapy. This was an open-label trial, noting that the combination of abiraterone + enzalutamide resulted in more grade 3 erectile dysfunction, hypertension, and fatigue, as well as more grade 3/4 liver function test elevations. The addition of enzalutamide to abiraterone increased toxicity, but did not have a discernable effect on efficacy, assessed as either metastasis-free survival or OS:

APCCC Ian Davis-2.jpg 

APCCC Ian Davis-3.jpg 

Dr. Davis concluded his presentation with the following take-home messages:

  • There is limited information so far with respect to ADT + docetaxel + additional systemic therapy
  • For TITAN and ARCHES, treatment was not concurrent and there was rapid sequencing
  • In ENZAMET, there is no OS benefit observed yet but reported data is only from 50% of planned events. Additionally, there is a strong PFS signal for triplet ADT + enzalutamide + docetaxel
  • In PEACE-1, there is an rPFS benefit with ADT + abiraterone + docetaxel both in high and low volume disease. Additionally, there is an OS benefit with ADT + abiraterone + docetaxel so far only shown in men with high-volume disease
  • In STAMPEDE, there was no benefit with the addition of enzalutamide to abiraterone, however with more toxicity
  • Although triplet therapy is intriguing we must establish the doublet therapies first

Presented by: Ian Davis, MBBS, PhD, FRACP, FAChPM, Medical Oncologist, Professor of Medicine, Head of the Eastern Health Clinical School, Monash University and Eastern Health in Melbourne, Australia

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 Advanced Prostate Cancer Consensus Conference, Saturday, October 9, 2021.


  1. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 2019 Jul 4;381(1):13-24.
  2. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy with Enzalutamide or Placebo in Men with Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019 Nov 10;37(32):2974-2986.
  3. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019 Jul 11;381(2):121-131.