ESMO 2023: How Much Systemic Treatment Is Needed and How Long?

(UroToday.com) The 2023 ESMO annual meeting included a session on the management of (very) high-risk localized prostate cancer, featuring a presentation by Dr. Gwenaëlle Gravis discussing how much and how long we should be giving systemic treatment. Dr. Gravis started by summarizing the current available literature for neoadjuvant treatments with radical prostatectomy for high risk prostate cancer, which to date has not been impressive:

Additionally, there is data with regards for adjuvant treatments with radical prostatectomy for high risk prostate cancer, including ADT, bicalutamide, mitoxantrone, and docetaxel:
When considering the current phase III clinical trials post-prostatectomy for high risk prostate cancer, we have the ERADICATE trial (ADT + darolutamide versus placebo) and the PROTEUS trial (apalutamide versus placebo.
With regards to ADT in combination with radiotherapy, we know that radiotherapy + ADT is superior to radiotherapy alone, and we know that radiotherapy + ADT is better than ADT alone:
Furthermore, radiotherapy + ADT for 36 months is superior to only 6 months of ADT: 
And more recently, we learned that radiotherapy + ADT for 36 months is not superior to ADT for 18 months with the end point of overall survival:

In 2022, the results of a MARCAP meta-analyses were published, which assessed 12 trials with individual patient data (n = 10,583) that evaluated use or prolongation of ADT, either in the neoadjuvant (3-4 to 6-9 months) or adjuvant settings (4-6 to 18-36 months).¹ After a median follow-up of 11.4 years (IQR: 9.0 – 15.0), the addition of long-term androgen suppression to both high-dose radiotherapy and low-dose radiotherapy improved overall survival in this group of patients:
When considering ADT + radiotherapy with or without docetaxel and the endpoint of failure free survival, a meta-analysis from Vale and colleagues found an 8% absolute reduction in failure (from 70% to 62%) at 4 years, with a pooled hazard ratio favoring standard of care + docetaxel of 0.70 (95% CI 0.61 - 0.81):²
However, when assessing the utilization of ADT + radiotherapy with or without docetaxel for high risk non-metastatic prostate cancer with overall survival as the endpoint, GETUG-12, STAMPEDE, and RTOG 0521 all did not demonstrate a benefit for the addition of docetaxel:

Importantly, the PEACE-2 phase III trial is assessing cabazitaxel and pelvic radiation in patients with high risk, localized prostate cancer. All 750 patients have completed accrual, with a primary endpoint of clinical recurrence free survival and several key secondary endpoints:

Dr. Gravis notes that in the STAMPEDE arm of high-risk localized prostate cancer treated with either abiraterone or enzalutamide, there was a consistent effect with ARPI regardless of metastatic burden.³ In this study, local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. There were 1,974 patients randomized and over a median follow-up of 72 months (IQR 60–84), metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR NE–NE) than in the control groups (not reached, 97–NE; HR 0.53, 95% CI 0.44–0.64). The 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group. Overall survival (median not reached [IQR NE–NE] in the combination-therapy groups vs not reached [103–NE] in the control groups; HR 0.60, 95% CI 0.48–0.73):
Considering radiotherapy and phase 3 clinical trials for high risk prostate cancer, there are several ongoing trials, including PEGASUS, ENZARAD, ATLAS, and ANZUP 1801:
Dr. Gravis emphasized that we would be remiss not to mention the consequences of ADT, particularly cumulative dosing, which include: (i) fatigue, (ii) erectile dysfunction/low libido, (iii) sarcopenic obesity, (iv) cognitive impairment and depression, (v) osteoporosis and fractures, and (vi) diabetes mellitus, dyslipidemia, metabolic syndrome, and cardiovascular events. Dr. Gravis notes that testosterone recovery after ADT and radiotherapy is quite variable. In fact, for men receiving 36 months of ADT, it may take 5 years to recovery testosterone and 50% of men will never recover testosterone function:
Dr. Gravis notes that artificial intelligence will more than likely play a role in selecting patients for ADT and duration of ADT treatment. At ASCO 2023, Dr. Andrew Armstrong presented results of a pooled analysis of multiple phase III NRG/RTOG trials aimed at developing and subsequently validating an AI-derived digital pathology-based biomarker to predict the benefit of long-term ADT addition to radiotherapy in men with localized, high-risk prostate cancer. The validation analysis in the NRG/RTOG 9202 cohort demonstrated that the ArteraAI biomarker was a significant predictor of the utility of long-term ADT use in this cohort (interaction p=0.04). As demonstrated below, patients in the biomarker negative group (n = 407) derived no benefit from long-term ADT use, compared to short-term ADT use (HR 1.06, 95% CI 0.61 – 1.84). Conversely, patients in the biomarker positive group had significant improvements in the distant metastasis rates with long-term ADT (HR 0.55, 95% CI 0.41 – 0.73). Accordingly, approximately 1/3 of men with high-risk prostate cancer could have safely avoided long-term ADT based on the results of this predictive biomarker analysis:
Dr. Gravis concluded her presentation discussing how much and how long we should be giving systemic treatment by emphasizing that we must focus on shared decision making with our patients when discussing treatment options for the management of high and very high risk prostate cancer, and with the following take-home points:

• There are no phase 3 data to support neoadjuvant treatment with radical prostatectomy
• In the adjuvant setting, ADT should be discussed for pN+ patients
• Radiotherapy + ADT is superior to radiotherapy alone or ADT alone
• The duration of ADT should be for >= 18 months but may depend on patient comorbidities and individual risk
• ADT + radiotherapy + abiraterone + prednisone for 2 years is superior to radiotherapy + ADT alone for high risk, STAMPEDE M0 patients
• There are clinical trials ongoing for new strategies for intensification and de-intensification:
  • New combination therapies
  • Biomarker stratification
  • New imaging
  • Digital pathology

Presented by: Gwenaëlle Gravis, MD, Institut Paoli-Calmettes, Aix-Marseille, Marseille, France

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.

References:

1. Kishan AU, Sun Y, Hartman H, et al. Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis. Lancet Oncol. 2022;23(2):304-316.
2. 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.
3. Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: A meta-analysis of primary results from two randomized controlled phase 3 trials of the STAMPEDE platform protocol. Lancet 2022 Jan 29;399(10323):447-460.