(UroToday.com) The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) meeting featured a session on the treatment for biochemical recurrence/PSA persistence, and a presentation by Dr. Ray McDermott discussing how best to manage patients with a second biochemical recurrence, without correlation on next-generation imaging, after salvage radiation and/or after metastases directed therapy. Dr. McDermott notes that there are several issues to consider in the second biochemical relapse setting, including:
- Is the patient still castrated?
- PSA doubling time
- Extent of prior therapy
- PSA level
- Time since prior therapy
- Life expectancy/co-morbidities
- Patient expectations
Dr. McDermott emphasized that it is important to check testosterone levels in these patients. A longitudinal study from Borque-Fernando et al.1 (2003-2019) assessed 203 patients with ADT over a median follow-up of 80 months. During follow-up, 25% of patients did not recover from castrate levels of testosterone (> 50 ng/dL), and 81% did not recover to normo-gonadal levels (>350 ng/dL). Predictors of testosterone recovery included duration of ADT and age at ADT cessation.
For these patients, the NCCN also highlights the need to assess the extent of prior therapy received:
For men with a PSA doubling time < 9 months, 50% of the EMBARK population had surgery and salvage radiotherapy with a median PSA of 5 ng/mL subsequently receiving ADT + enzalutamide or enzalutamide monotherapy. Based on the trial design of EMBARK,2 intermittent therapy is appropriate, however, the utility of additional metastasis-directed therapy is unknown. Dr. McDermott notes that the EORTC 2391 – ESCALATE-RT phase 3 randomized trial is comparing metastasis targeted therapy versus no further treatment in patients treated with an ARPI in monotherapy for high-risk PSA relapse after local therapy. The control arm will be darolutamide 600 mg BID for 9 months, which is suspended if the PSA is <= 0.2 ng/mL, followed by PSA monitoring until progression. The experimental arm will be darolutamide 600 mg BID for 9 months, which is suspended if the PSA is <= 0.2 ng/mL + metastasis-directed therapy/whole pelvis radiotherapy, followed by PSA monitoring until progression. Metastasis-directed therapy will comprise 3 x 10 Gy or 5 x 7 Gy or 5 x 7 Gy or other equivalent ablative fractionations as per local standard using stereotactic body radiotherapy. Whole pelvis radiotherapy includes 44-54 Gy in 1.8-2 Gy per fraction, as per local standard with SIB boost to the positive nodes. The primary endpoint is time to disease progression, with the following trial design:
For patients with a PSA doubling time > 9 months, it is crucial to assess the PSA level, the extent of prior therapy, and the time since prior therapy. Dr. McDermott highlighted the TOAD trial, which assessed when to initiate ADT in patients with biochemical recurrence.3 This was a phase III randomized trial that randomized 293 men to immediate ADT vs deferred ADT (delay of at least 2 years). Over a median follow-up of 5 years, among patients with biochemical relapse, there was no significant difference in overall survival (HR 0.58, 95% CI 0.30-1.12, p = 0.10). In fact, 41% of patients never started ADT at 5 years after biochemical recurrence:
Fendler and colleagues also assessed 68Ga-PSMA-11 PET/CT accuracy in a prospective multicenter trial among 635 patients with biochemically recurrent prostate cancer after prostatectomy (n = 262, 41%), radiation therapy (n = 169, 27%), or both (n = 204, 32%).4 On a per-patient basis, positive predictive value was 0.84 (95% CI, 0.75-0.90) by histopathologic validation and 0.92 (95% CI, 0.88-0.95) by the composite reference standard (n = 217), with 68Ga-PSMA-11 PET/CT localizing recurrent prostate cancer in 475 of 635 (75%) patients. The detection rates stratified by PSA are as follows:
Finally, Mjaess et al.5 previously assessed if there is a role for repeating PSMA PET/CT after a negative scan in biochemical recurrent prostate cancer. Among 29 patients with a first negative PSMA PET/CT for biochemical recurrence that subsequently had a follow-up PSMA PET/CT for further PSA progression. Overall, 12/29 (41.3%) of patients had a positive second PSMA PET/CT, 3/29 (10.3%) showing local recurrence, and 7/29 (24.1%) showing lymph node recurrence. Treatment change occurred in 6/29 (20.6%) patients:
Dr. McDermott concluded his presentation discussing how best to manage patients with a second biochemical recurrence, without correlation on next-generation imaging, after salvage radiation and/or after metastases directed therapy with the following take-home messages:
- For patients with a PSA doubling time < 9 months: treat systemically +/- metastasis directed therapy
- For patients with PSA doubling time > 9 months:
- Be patient
- Do not do a PSMA PET/CT too soon, or repeat the study if negative
- Review of the whole pelvis has been previously treated
- Metastasis-directed therapy may significantly delay the need for hormone deprivation therapy
- Intermittent hormone therapy is likely the most appropriate
Presented by: Professor Ray McDermott, MD, PhD, St. Vincent’s University Hospital and Cancer Trials Ireland, Dublin, Ireland
Written by: Zachary Klaassen, MD, MSc - Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Advanced Prostate Cancer Consensus Conference (APCCC) Meeting, Lugano, Switzerland, Thurs, Apr 25 - Sat, Apr 27, 2024.
References:
- Borque-Fernando A, Estrada-Dominguez F, Esteban LM, et al. Testosterone recovery after androgen deprivation therapy in prostate cancer: Building a predictive model. World J Mens Health. 2023 Jan;41(1):129-141.
- Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med 2023 Oct 19;389(16):1453-1465.
- Duchesne GM, Woo HH, Bassett JK, et al. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): A randomized, multicentre, non-blinded, phase 3 trial. Lancet Oncol 2016;17(6):727-737.
- Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncol 2019 Jun 1;5(6):856-863.
- Mjaess G, Vierasu I, Lacroix S, et al. Is there a role for repeating PSMA PET/CT after a negative scan in biochemical recurrent prostate cancer? Acta Oncol. 2020 Nov;59(11):1397-1400.