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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.


References:

  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-