EAU 2024: Options and Challenges in the Management of Oligometastatic Prostate Cancer in the PSMA-PET Era

(UroToday.com) The 2024 European Association of Urology (EAU) annual meeting featured a meeting of the EAU Section of Oncologic Urology (ESOU) and a presentation by Dr. Christopher Sweeney discussing options and challenges in the management of oligometastatic prostate cancer in the PSMA-PET era. Dr. Sweeney notes that one of the biggest challenges associated with oligometastatic prostate cancer is the definition of oligometastasis: “disease that can be eradicated with surgery or ablative radiotherapy and render a patient no evidence of disease without systemic therapy.” However, there is variable prognosis with ADT alone, such as nodal/bone/lung usually being rather indolent versus liver, and synchronous versus metachronous disease:

Additionally, is the challenge of defining cut-points, and a challenge achieving the right balance between futile and/or quality of life impairing therapy versus maximal clinical benefit with minimal toxicity. Defining imaging cut-points is also challenging, given that more often than not, what we see on imaging (even on molecular imaging) is just the tip of the iceberg.

SBRT for “oligometastatic” disease has been assessed in the STOMP and ORIOLE trials. In STOMP,¹ patients were included if they were conventional scan negative for metachronous disease, but choline PET positive (<= 3 extracranial lesions), and then randomized to SBRT versus observation. Although the hazard ratio favored metastasis directed SBRT (HR 0.60), the 95% CI was 0.31 to 1.13, p = 0.11. In the ORIOLE trial,² patients were assessed by PSMA PET, and in those that had treatment of all PSMA positive lesions versus those that did not, there was a benefit in PFS for complete eradication: HR 0.26, 95% CI 0.09-0.76:

In 2022, the STOMP and ORIOLE investigators combined data, assessing for genetic predictors of long-term response.³ In this analysis, high-risk pathogenic somatic mutations included those in ATM, BRCA1/2, Rb1, and p53. Those with a high-risk mutation had a median PFS after metastasis directed therapy of 7.5 months versus 13.4 months for those without a high-risk mutation:

So, what is the best treatment plan for disease occult to molecular imaging (micrometastatic on PSMA PET/CT)? Below the surface there may be (i) no disease, (ii) contained by innate immune surveillance, or (iii) alive but a dormant tumor. The goal for these patients is to match the treatment plan to the disease biology. Dr. Sweeney notes that based on the CHAARTED⁴ and STOPCaP⁵ 2023 individual patient data meta-analysis [5], there is no clear benefit to docetaxel for low volume disease, whether these patients are synchronous or metachronous:

However, there is a clear benefit for combination therapy with ADT + ARSI in low volume patients, for both synchronous and metachronous patients, based on data from ENZAMET⁶ and TITAN⁷:

With regards to SBRT + ADT for oligometastatic disease, the EXTEND trial⁸ was published in 2023 and assessed 6 months of ADT +/- SBRT for patients with conventional scan metachronous oligometastatic HSPC. This trial found a progression free survival benefit for the addition of ADT compared to SBRT alone (HR 0.25, 95% CI 0.12-0.55):

In work from Dr. Sweeney’s group recently accepted to Eur Urol Oncol, based on the Movember Consortium, they assessed a multi-institutional analysis of metastasis directed therapy with or without ADT in oligometastatic castration sensitive prostate cancer. Among this retrospective review of consecutive patients treated with metastasis directed therapy, metastasis directed therapy + ADT was used for 23% of synchronous patients, and metastasis directed therapy alone was used in 1% of synchronous patients. Combination therapy was associated with improved biochemical PFS and eugonadal PFS versus metastasis directed therapy alone:

Finally, Dr. Sweeney noted several trials in the oligometastatic HSPC disease space:

Dr. Sweeney concluded his presentation by discussing options and challenges in the management of oligometastatic prostate cancer in the PSMA-PET era by highlighting an “ideation” to be confirmed or refuted with prospective trials:

• Treat the disease we can see with best ablative therapy:
  • Maximum efficacy and least treatment burden
  • Surgery and/or radiation to all disease including the prostate primary if synchronous disease
  • Optimal cut-points to be defined
• Treat the disease we cannot see with the best systemic therapy
  • Micro-metastatic on PSMA PET/CT
  • Possibly ADT + ARSI for two years (plus targeted treatment ie. PARP inhibition if there is a BRCA mutation)
  • Two year based on data in adjuvant high risk localized disease
• Stop therapy at 2 years, testosterone recovery, no recurrence
  • Disease eradicated and die of non-prostate cancer death years later
  • Testosterone replacement if not recovery to a eugonadal state
  • Restart systemic therapy if disease recurs

Presented by: Christopher J. Sweeney, MBBS, South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia

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. Ost P, Reynders D, Decaestecker K, et al. Surveillance of metastasis-directed therapy for oligometastatic cancer recurrence: A prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018 Feb 10;36(5):446-453.
2. Phillips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol 2020 Mar 26;6(5):650-659.
3. Deek MP, Van der Eecken K, Sutera P, et al. Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic prostate cancer: Analysis of STOMP and ORIOLE trials. J Clin Oncol. 2022;40(29):3377-3382.
4. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol 2018 Apr 10;36(11):1080-1087.
5. Vale CL, Fisher DJ, Godolphin PJ, et al. Which patients with metastatic hormone sensitive prostate cancer benefit from docetaxel: A systematic review and meta-analysis of individual participant data from randomized trials. Lancet Oncol. 2023 Jul(7):783-797.
6. Sweeney CJ, Martin AJ, Stockler MR, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): An international, open-label, randomized, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):323-334.
7. Merseburger AS, Agarwal N, Bhaumik A, et al. Apalutamide plus androgen deprivation therapy in clinical subgroups of patients with metastatic castration-sensitive prostate cancer: A subgroup analysis of the randomized clinical TITAN study. Eur J Cancer. 2023 Nov;193:113290.
8. Tang C, Sherry AD, Haymaker C, et al. Addition of metastasis-directed therapy to intermittent hormone therapy for oligometastatic prostate cancer: The EXTEND phase 2 randomized clinical trial. JAMA Oncol. 2023 Jun 1;9(6):825-834.