APCCC 2021: What Is the Evidence for “Triplet Therapy” (ADT + Radiation of the Primary + Additional Systemic Therapy)?

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

Dr. Fizazi started by highlighting that there is level 1 evidence demonstrating a survival benefit of docetaxel in mHSPC. This was highlighted in 2016 by a systematic review and meta-analysis by Vale et al.,1 assessing data from CHAARTED, GETUG-15, STAMPEDE (standard of care +/- docetaxel), and STAMPEDE (standard of care + zoledronic acid +/- docetaxel. Overall, based on 2,993 men and 1,254 deaths, there was a 23% reduction in mortality when combining standard of care + docetaxel versus standard of care alone:

APCCC Fizazi-0.jpg 

Dr. Fizazi notes that this has resulted in a 10% absolute improvement in survival (from 40% to 50%) at four years of follow-up.

There is also level 1 evidence for abiraterone in the mHSPC disease space. The LATITUDE trial, published in 2017, evaluated abiraterone + ADT compared to ADT alone among men with high-risk mHSPC.2 Patients were randomized 1:1 to either abiraterone + ADT (1000 mg abiraterone acetate + 5mg prednisone daily) (n=597) or ADT + placebo (n=602). The co-primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS). Over a median follow-up of 30.4 months, patients treated with abiraterone + ADT had a 38% risk reduction of death (HR 0.62, 95%CI 0.51-0.76) compared to ADT + placebo. There was also a 53% risk of reduction of radiographic progression or death for patients treated with abiraterone + ADT compared to ADT alone (HR 0.47, 95%CI 0.39-0.55).

The STAMPEDE trial arm G also assessed abiraterone, including men with locally advanced or metastatic prostate cancer (newly diagnosed N1 or M1 disease), or any two of the following: stage T3/4, PSA ≥ 40 ng/mL, or Gleason score 8-10.3 These patients were randomized 1:1 to standard of care (ADT for ≥2 years, n=957) vs ADT + placebo (1000 mg abiraterone acetate + prednisone 5 mg daily, n=960). The primary outcomes were OS and failure-free survival (FFS), where failure was defined as PSA failure, local failure, lymph node failure, distant metastases, or prostate cancer death. Over a median follow-up of 40 months, there was a 37% relative improvement in OS (HR 0.63, 95%CI 0.52-0.76) favoring abiraterone + ADT. Furthermore, abiraterone + ADT demonstrated a 71% improvement in FFS (HR 0.29, 95%CI 0.25-0.34).

Prostate radiotherapy has also been assessed in mHSPC, specifically in the STAMPEDE trial arm H.4 This study randomized 2,061 men to either standard systemic treatments (ADT +/- chemotherapy) versus standard systemic treatments (ADT +/- chemotherapy) plus radiotherapy to the primary tumor. There were 819 (40%) men that had a low metastatic burden, 1,120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved FFS (HR 0.76, 95% CI 0.68-0.84) but not OS (HR 0.92, 95% CI 0.80-1.06). However, in a prespecified subgroup analysis, patients receiving radiotherapy to the prostate among patients with low metastatic burden, there was a significant improvement in OS (HR 0.68, 95% CI 0.52-0.90):

APCCC Fizazi-1.jpg 

The PEACE-1 trial aimed to randomize mHSPC men 1:1:1:1 to standard of care vs standard of care + abiraterone vs standard of care + radiotherapy vs standard of care + abiraterone + radiotherapy. The trial schema of PEACE-1 is as follows:

APCCC Fizazi-2.jpg 

First presented at the 2021 ASCO meeting, the results from PEACE-1 showed that adding abiraterone to ADT + docetaxel significantly improved rPFS in men with mHSPC (HR: 0.50 (0.40-0.62), p<0.0001). Updated data was subsequently presented at ESMO 2021. Over a median follow-up of 4.4 years, 273 death events were observed in the ADT + docetaxel population. In terms of the co-primary endpoint of rPFS in the population who received docetaxel as standard of care demonstrated a significant benefit to the addition of abiraterone (HR 0.50, 95% CI .40-0.62). This effect was seen regardless of disease burden, with benefits in the high volume (HR 0.47, 95% CI 0.36-0.60) and low volume (HR 0.58, 95% CI 0.39-0.87) cohorts. Additionally, OS was also improved with the addition of abiraterone in the overall study population (HR: 0.83, 95% CI: 0.69-0.99, p=0.034; medians: 5.7 vs 4.7 years).

Dr. Fizazi notes that data is not yet mature in the PEACE-1 radiotherapy arm, but highlights that there are 502 patients with low-volume disease in this group. Of note, there is some literature to support the combination of abiraterone with radiotherapy from the GETUG/GEP phase 1 study.5 In this trial, abiraterone was given during one month before salvage radiotherapy at 1000 mg PO once daily, then 750 mg (Dose Level 1, DL1) or 1000 mg (DL2) for 5 months combined with 6-months of goserelin on the first day of radiation (neoadjuvant scheme) or one month before starting salvage radiotherapy (concomitant scheme). In the neoadjuvant scheme at DL1, 2/9 patients did not achieve castration levels of testosterone, and 4/9 patients presented with grade 3 liver enzyme elevation. In the concomitant scheme, testosterone dropped to undetectable levels, and at DL1 (n=6) there were no dose-limiting toxicities.

Data combining docetaxel with radiotherapy to the primary lesion is based mostly on sequential data, including (i) PEACE-1 (docetaxel first, then radiotherapy: 50%), (ii) STAMPEDE (18% of patients in the 2018 radiotherapy report4), and (iii) multiple trials in high-risk localized prostate cancer (GETUC-12, STAMPEDE, RTOG, SPCG, etc). Concomitant docetaxel (20 mg/m2) + radiotherapy (70 Gy) has been tested in a phase 2 trial,6 with no new safety signals.

Dr. Fizazi notes that combining treatments in mHSPC, in addition to ADT, remains to be completely elucidated as highlighted in the following figure:

APCCC Fizazi-3.jpg 

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

  • Existing data supports combining several systemic treatments in M1 castration-sensitive prostate cancer: ADT + docetaxel + abiraterone/prednisone
  • Combining intensified systemic treatments with local radiotherapy in men with low volume disease makes sense but there is currently no evidence from randomized clinical trials. The PEACE-1 analysis for the radiotherapy question should clarify this question, hopefully by 2023

Presented by: Karim Fizazi, MD, PhD, Department of Medical Oncology, Institut Gustave Roussy, University of Paris Sud, Paris, France

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. Vale CL, Burdett S, Rydzewska LHM, et al. Addition of docetaxel or bisphosphonates to standard of care in men with localized or metastatic, hormone-sensitive prostate cancer: A systematic review and meta-analyses of aggregate data. Lancet Oncol. 2016;17(2):243-256.
  2. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377:352-60.
  3. James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377:338-51.
  4. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
  5. Supiot S, Campion L, Pommier P, et al. Combined abiraterone acetate plus prednisone, slavage prostate bed radiotherapy and LH-RH agonists (CARLHA-GEP12) in biochemically-relapsing prostate cancer patients following prostatectomy: A phase I study of the GETUG/GEP. Oncotarget. 2018 Apr 24;9(31):22147-22157.
  6. Bolla M, Hannoun-Levi JM, Ferrero JM, et al. Concurrent and adjuvant docetaxel with three-dimensional conformal radiation therapy plus androgen deprivation for high-
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