ASTRO 2021: Is Metastasis-Directed Therapy the Wave of the Future in Oligo-mCRPC?

(UroToday.com) The 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting included a Prostate Cancer Oligometastases session and a presentation by Dr. Matthew Deek discussing whether metastasis-directed therapy is the wave of the future for oligometastatic castration-resistant prostate cancer (CRPC).


Dr. Deek started by highlighting a case presentation of a 64-year-old man with pT3aN0M0R1, Gleason 4+5=9 prostate adenocarcinoma s/p radical prostatectomy in 2012 followed by salvage radiotherapy to 68.4 Gy in 2013. He then developed CRPC treated with enzalutamide, followed by oligoprogression with a rising PSA and a growing right external iliac lymph node in 2015. Historically, therapy for CRPC has been systemic therapy, including enzalutamide, abiraterone, darolutamide, radium-223, sipuleucel-T, docetaxel and cabazitaxel, as highlighted by Dr. Deek. But what is the role of local therapies in this setting?

Unlike the metastatic hormone sensitive setting, Dr. Deek notes that there is very little prospective data in the mCRPC setting for metastasis directed therapy. One such study, the ICE-PAC study, was published recently in European Urology,1 testing the efficacy and safety of the PD-L1 inhibitor avelumab with stereotactic ablative body radiotherapy in mCRPC. This was a prospective phase 2 study enrolling 31 men with progressive mCRPC after at least one prior androgen receptor–directed therapy. Patients received avelumab 10 mg/kg intravenously every 2 weeks for 24 weeks (12 cycles), and a single fraction of stereotactic ablative body radiotherapy (20 Gy) was administered to one or two disease sites within 5 days before the first and second avelumab treatments. Over a median follow-up of 18 months, the disease control rate was 48% (95% CI 30–67%) and the objective response rate was 31% (95% CI 11–59%). Median rPFS was 8.4 months (95% CI 4.5–NR) and median OS was 14.1 months (95% CI 8.9–NR):

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Currently, there are several ongoing trials assessing the utility of metastasis-directed therapy in the mCRPC setting: 

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A unique CRPC state is the oligoprogressive mCRPC disease state whereby several of the oligometastatic lesions are growing. When Dr. Deek was at Johns Hopkins University, he was part of a study that looked at their institutional experience where men with oligoprogressive (<= 5 lesion) mCRPC were treated with metastasis-directed therapy.2 Patients with oligoprogressive CRPC were retrospectively evaluated, and outcomes following metastasis-directed therapy were reported. Among 68 included patients, 78% experienced a PSA decline, and PSA nadired to undetectable in 29% of patients. The likely ideal paradigm is to add metastasis-directed therapy to systemic therapy for oligoprogressive mCRPC. In their paper,2 Dr. Deek notes that clinical outcomes improved with metastasis-directed therapy over systemic therapy alone. Specifically, when comparing patients that received metastasis-directed therapy versus those that did not, there was an improvement in:

  • PSA failure: 9.7 vs 4.2 months (p = 0.066)
  • Time to next intervention: 14.9 vs 8.8 (p = 0.025)
  • Distant metastasis free survival: 12.7 vs 8.9 months (p = 0.05)

Another paradigm is based on the theory that there are resistant clones that have not responded to systemic therapy and these are the lesions that are progressing. So, if the same systemic therapy is continued, keeping the majority of lesions in check, perhaps stereotactic ablative radiotherapy is able to treat those lesions that have progressed (oligo-progressed). Again, there is data from Dr. Deek’s study2 to suggest that this is feasible. They found that outcomes were similar after metastasis-directed therapy in those who remained versus those that changed therapy:

  • PSA failure: 9.6 vs 11.6 months (p = 0.36)
  • Time to next intervention: 15.6 vs 12.3 (p = 0.92)
  • Distant metastasis free survival: 10.8 vs 11.8 months (p = 0.63)

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Given that this is a hot topic of investigation, there have been several retrospective studies published over the 2-3 years. To summarize these studies, Dr. Deek notes that time to next intervention is quite similar ranging from 8.6-17 months, but with the majority of studies noting 16-17 months:

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Dr. Deek concluded his presentation by reverting back to the case presentation. This patient was treated with stereotactic ablative radiotherapy (6 Gy x 5) and remained on enzalutamide for 5 years after therapy. He did have an oligoprogression of one lesion by the right common iliac lymph node in 2020, which was successfully treated with further metastasis directed therapy. 

Presented by: Matthew Deek, MD, Department of Radiation Oncology, Rutgers University, New Brunswick, NJ

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 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting, Sat, Oct 23 – Wed, Oct 27, 2021.

References:

  1. Kwan EM, Spain L, Anton A, et al. Avelumab combined with stereotactic ablative body radiotherapy in metastatic castration-resistant prostate cancer: The Phase 2 ICE-PAC Clinical Trial. Eur Urol. 2021 Sept 4 [Epub ahead of print].
  2. Deek MP, Taparra K, Phillips R, et al. Metastasis-directed therapy prolongs efficacy of systemic therapy and improves clinical outcomes in oligoprogressive castration-resistant prostate cancer. Eur Urol Oncol. 2020 Jun 11 [Epub ahead of print].
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