Basel, Switzerland ( At the APCCC 2019 session on prostate-specific antigen (PSA) recurrence after radical local therapy and oligometastatic prostate cancer, Dr. Eric Small from UCSF discussed treatment of oligometastatic and oligoprogressive CPRC. Oligometastatic CRPC is defined as a limited number of metastases in a patient who has ADT-refractory prostate cancer, whereas oligoprogressive CRPC is defined as CRPC disease progression that has manifested as new oligometastases (some argue also in patients with pre-existing metastases). However, the identification of pre-existing metastases is dependent on the imaging modality, timing, and frequency of imaging. Dr. Small argues that instead of oligoprogressive CRPC, two other definitions should be used: (i) synchronous oligometastatic CRPC – metastases are synchronous with the emergence of ADT resistance, and (ii) metachronous oligometastatic CRPC – (new) metastases follow the clinical emergence of ADT resistance.

According to Dr. Small, there are many unanswered questions regarding oligometastatic CRPC, several which are shared with hormone naïve prostate cancer:

  • What is the cutpoint between oligometastatic and polymetastatic disease?
  • What is the optimal imaging technology to identify oligometastatic disease?
  • What is the optimal timing and frequency of imaging?
  • Does the modality of oligometastatic disease ablation matter?

Questions that are unique to the CRPC disease state:

(i) Does it matter if oligometastatic lesions are synchronous or metachronous?

For oligometastatic lesions that are synchronous with CRPC, there are more systemic therapeutic options, but are these patients more radiosensitive than patients with metastases later in the disease? Ablation of early CRPC clones that have developed metastatic potential may delay the progression to a more subclonal cancer. For patients with oligometastatic lesions that are metachronous have fewer systemic therapeutic options if the CRPC has already been treated. A question that remains is whether the radiobiology is different than in patients whose CRPC has just emerged? It is likely that a subclonal cancer has already been established and ablation of these metastases won’t affect clonal evolution.

(ii) What is the role of changing/adding systemic therapy?

Dr. Small presented a case of a classic patient with non-metastatic CRPC (nmCRPC), noting that in 2019 they will get either apalutamide, enzalutamide, or darolutamide – what he coins the “SPA” treatment (SPARTAN, PROSPER, ARAMIS). But, what if prior to “SPA” treatment the patient had a PSMA PET-CT that diagnosed oligometastatic disease? Higher sensitivity imaging modalities will further reduce the proportion of patients with “non-metastatic” CRPC, and it remains to be fully elucidated how likely PSMA PET-CT is to reveal metastases in nmCRPC SPA-like patients. In a study submitted for publication, 29% of patients eligible for “SPA” treatment had oligometastatic disease on PSMA PET-CT imaging. Ultimately, we have level 1 evidence supporting the use of next generation AR inhibitors in nmCRPC men who are very likely to have oligometastatic disease on functional imaging.

(iii) What is the utility of local ablative radiotherapy (without systemic therapy) to control oligometastatic CRPC?

In a retrospective, exploratory study, Lohaus et al.assessed the efficacy of PSMA-PET-guided local ablative radiotherapy among 15 patients with oligometastatic CRPC. They noted that PSA response was observed in 11 patients (73%) and mean time to PSA progression or last follow-up was 17.9 months, as opposed to 2.9 months estimated from the PSA doubling time without ablative radiotherapy (p<0.001). Another study analyzed 101 patients with CRPC who underwent whole-body diffusion-weighted MRI when a new line of anticancer therapy was being considered2. For oligoprogressive CRPC, progressive site directed therapy with radiation therapy and unchanged continuation of systemic therapy were recommended. This study had 38 patients with oligoprogressive CRPC, and 23 (61%) that underwent progressive site directed therapy. A decrease in PSA levels of at least 50% in response to progressive site directed therapy was observed in 16 cases (70%), and the median time to PSA progression was 8.7 months. A 50% PSA decline was achieved in 16 of the 18 patients with intrapelvic oligoprogressive CRPC (89%) and in none of the five patients with non-intrapelvic oligoprogressive CRPC.

Dr. Small concluded with a few take-home messages:

  • Ablative radiotherapy of both synchronous and metachronous oligometastatic CRPC is feasible and safe
  • There are provocative data, but it is very premature as there is no prospective, comparative data to suggest that ablative radiotherapy is beneficial
  • Further, there is no prospective data to compare ablative radiotherapy (or surgery) in synchronous vs metachronous metastatic disease
  • There is no prospective data to define the role of adding ablative therapy to systemic therapy

Presented by: Eric J. Small, MD, University of California at San Francisco, San Francisco, California

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 – 31, 2019 in Basel, Switzerland

1. Lohaus F, Zophel K, Lock S, et al. Can Local Ablative Radiotherapy Revert Castration-resistant Prostate Cancer to an Earlier Stage Disease? Eur Urol 2019 Apr;75(4):548-551.

2. Yoshida S, Takahara T, Arita Y, et al. Progressive Site-Directed Therapy for Castration-Resistant Prostate Cancer: Localization of the Progressive Site as a Prognostic Factor. Int J Radiat Oncol Biol Phys 2019 June 12 [Epub ahead of print].