(UroToday.com) The 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting included a session on the management of metastatic hormone sensitive prostate cancer (mHSPC) and a presentation by Dr. Bertrand Tombal discussing de-escalation strategies in mHSPC. Dr. Tombal started his presentation by highlighting the current landscape of advanced prostate cancer as it stands in 2022:
Dr. Tombal then illustrated two clinical cases of high-risk patients (PSA > 40 ng/mL, T3a, Gleason >=8) in order to highlight how heterogeneous staging is and how it affects treatment. Patient #1 had several right common iliac positive nodes, was staged as N1M0 and received radiotherapy to the prostate + 2 years + abiraterone. Patient #2 had several bone mets in the T-spine, was staged as N0M1b and subsequently received radiotherapy to the primary (+/- metastasis directed therapy) + ADT + ARTA until disease progression (which may be a long, long time). Thus two, very similar clinical pictures, but patient #1 having a finite treatment schedule, and patient #2 having perhaps prolonged (or even lifelong) therapy. According to the EMA, treatment optimization is “a process intended to enhance the long-term efficacy, adherence, safety, convenience, and affordability of a therapy. Its ultimate goal is to expand access to effective treatment to all of those it will benefit.” So, the question is: What is the optimal duration of ADT and/or ARTA to be administered to obtain a similar efficacy while improving health-related quality of life and reduce resource utilization? Can we use intermittent regimens in selected patients? ADT + ARTA, ADT + ARTA followed by ADT alone, ADT + ARTA followed by ARTA?
Looking back at the historic intermittent versus continuous ADT in prostate cancer data, Dr. Tombal highlighted the 2013 study by Hussain et al. [1] that enrolled 3,040 patients with mHSPC, with good performance status (0-2), and PSA >= 5 ng/mL. Patients were subsequently treated with 7 months of goserelin + bicalutamide, and after 7 months of complete androgen blockade, 1,535 eligible men achieved a PSA <= 4.0 ng/mL. Among these men, 765 were then randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. Over a median follow-up of 9.8 years, the median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (HR for death with intermittent therapy, 1.10; 90% CI 0.99 to 1.23):
A subsequent systematic review of 4 randomized trials found no difference between intermittent androgen blockade and continuous androgen blockade (HR 1.02, 95% CI 0.93-1.11). Several studies have subsequently shown that intermittent ADT is associated with improved physical capacity and improved sexual function. When assessing the minimal duration of ADT and/or ARTA to be administered Dr. Tombal believes that we can use intermittent regimens in selected patients.
Perhaps there are indications based on PSA response for which patients we may be able to assess for treatment de-escalation. Data from the SWOG 9346 (INT-0162) trial demonstrated that PSA after ADT is a strong independent predictor of survival in new metastatic prostate cancer [2]. As follows is the overall survival by PSA status at the end of ADT induction, notably with worse survival for PSA > 4.0 vs 0.2 < PSA <= 4.0 vs PSA <= 0.2:
Additionally, seven-month PSA is prognostic in mHSPC treated with ADT with or without docetaxel as reported in a follow-up study from the CHAARTED data [3]:
Furthermore, work presented at ASCO 2020 suggests that PSA kinetics among patients treated with apalutamide in the TITAN trial was associated with improved rPFS, specifically PSA50 response and 6 month depth of PSA response:
But is PSA enough? Perhaps not. Going back to the aforementioned cases, Dr. Tombal notes that for patient #1, his PSA after radiotherapy to the prostate and lymph nodes + ADT was 0.1 ng/mL, however less than 1 year later his PSA was up to 7 ng/mL with diffuse metastatic disease.
Dr. Tombal concluded his presentation of treatment de-escalation in mHSPC with the following take-home messages:
- There is clearly an opportunity to optimize/de-escalate intensified treatment in selected patients
- This requires a proper trial, as we should not break the equipoise simply because we believe or do not believe a concept
- These trials will be long and difficult (obtaining funding), but we should do them
Presented By: Bertrand Tombal, MD, PhD, Cliniques Universitaires Saint Luc, Brussels, Belgium
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 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Annual Hybrid Meeting, Lugano, Switzerland, Thurs, Apr 28 – Sat, Apr 30, 2022.
References:- Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med 2013;368:1314-1325.
- Hussain M, Tangen CM, Higano C, et al. Absolute Prostate-Specific Antigen value aftter androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: Data from the Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol. 2016 Aug 20;24(24):3984-3990.
- Harshman LC, Chen YH, Liu G, et al. Seven-Month Prostate-Specific Antigen is Prognostic in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation with or Without Docetaxel. J Clin Oncol. 2018 Feb 1;36(4):376-382.