EAU 2024: High-Risk Biochemical Recurrence After Radical Prostatectomy and Negative PSMA PET: What to Do? Systemic Therapy Alone

(UroToday.com) The 2024 European Association of Urology (EAU) annual meeting featured a plenary session on personalized approaches in high-risk and metastatic prostate cancer, and a presentation by Dr. Antti Rannikko discussing systemic therapy alone for patients with high-risk biochemical recurrence after radical prostatectomy and negative PSMA PET.

Dr. Rannikko states that patients typically have had salvage radiotherapy at this stage already, thus they most likely were lost to follow-up or had poor compliance with follow-up. Therefore, we must consider (i) when not to give salvage radiotherapy, (ii) what is the optimal systemic therapy, (iii) if these are young/healthy/asymptomatic patients – do we give them lifelong treatment?

When not to give radiotherapy is as important as when to give radiotherapy. In men with a high PSA and advanced prostate cancer on conventional imaging, tumor volume makes a difference. Radiotherapy is not beneficial if there is a high tumor volume (ie. >3 and no visceral metastasis).¹ In men with low PSA and non-metastatic prostate cancer on conventional imaging, PSA can be used as a surrogate for tumor volume. Salvage radiotherapy has been considered the only potentially curative therapy after biochemical failure and has been associated with better outcomes if given at lower PSA levels. In fact, Tilki and colleagues showed that salvage radiotherapy when given at a PSA equal to or lower than 0.25 ng/mL is associated with improved all cancer-mortality:²

When considering high risk biochemical recurrence and micrometastasis, it is important to delineate local or distant disease. Predictors of distant disease include: (i) Gleason Grade 3, (ii) positive margin status, (iii) pT3a, (iv) fast PSA doubling time (ie. < 6 months). If salvage therapy alone is not enough, should we add systemic treatment? According to Dr. Rannikko states, yes, we should. If pre-salvage radiotherapy PSA is >0.61 ng/mL, adding systemic therapy (bicalutamide 150 mg x 24 months) to salvage radiotherapy improves outcomes in metastasis free survival.³ There are several additional questions that arise, according to Dr. Rannikko:

1. Does this imply that in these high-risk men with biochemical recurrence, systemic treatment is needed to control micro-metastatic disease?
2. Should we then consider ARSIs as they are proven beneficial later in the prostate cancer trajectory?

Dr. Rannikko then discussed the recently published PRESTO trial which evaluated whether androgen deprivation therapy (ADT) improves outcomes in biochemically recurrent prostate cancer. The trial design for PRESTO is as follows:⁴

Among 503 patients, the median PSA was 1.8 ng/mL (IQR, 1.0-3.6), and at the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median 24.9 months for ADT + apalutamide vs 20.3 months for ADT; HR 0.52, 95% CI 0.35 to 0.77; median, 26.0 months for ADT + apalutamide + abiraterone vs 20.0 months for ADT; HR 0.48, 95% CI, 0.32 to 0.71). The PSA progression free survival curve for ADT + apalutamide vs ADT alone is as follows:
EMBARK showed us that adding enzalutamide to ADT, with a single treatment holiday at 9 months for responders (ie. PSA < 0.2 ng/mL) improves metastasis free survival.⁵ Similar findings were noted for enzalutamide monotherapy. Thus, several questions from this trial arise:

• Use in intermittent systematic therapy?
• When to start and the role of PET imaging?

Finally, since 2012, we have known that an intermittent approach to androgen deprivation for men with a rising PSA level after definitive radiotherapy does not result in inferior survival, as compared to continuous androgen blockade, with some noted quality of life benefits.⁶  

Dr. Rannikko concluded his presentation discussing systemic therapy alone for patients with high-risk biochemical recurrence after radical prostatectomy and negative PSMA PET with the following conclusions:

• The patient may be past the window of curability for salvage radiotherapy already
• Intermittent enzalutamide monotherapy may be best to limit harm
• However, when do patients start therapy?

Presented by: Antti S. Rannikko, MD, PhD, FEBU, University of Helsinki Helsinki, Finland

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 European Association of Urology (EAU) annual congress, Paris, France, April 5^th - April 8^th, 2024

References:

1. Ali A, Hoyle A, Haran AM, et al. Association of bone metastatic burden with survival benefit from prostate radiotherapy in patients with newly diagnosed metastatic prostate cancer: A secondary analysis of a randomized clinical trial. JAMA Oncol. 2021 Apr 1;7(4):555-563.
2. Tilki D, Chen MH, Wu J, et al. Prostate-Specific Antigen Level at the Time of Salvage Therapy After Radical Prostatectomy for Prostate Cancer and the Risk of Death. J Clin Oncol. 2023 May 1;41(13):2428-2435.
3. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med 2017;376(5):417-428.
4. Aggarwal R, Heller G, Hillman DW, et al. PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients with High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19). J Clin Oncol. 2024 Apr 1;42(10):1114-1123.
5. 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.
6. Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 2012;367(10):895-903.