ESMO 2021: PRORADIUM: Prospective Analysis of the Impact of Germline Mutations in Homologous Recombination Genes on the Response to Radium-223 for Metastatic Castration Resistant Prostate Cancer

(UroToday.com) In the on-demand poster session of the European Society for Medical Oncology (ESMO) Annual Congress, Dr. Elena Castro presented results from the PRORADIUM cohort (NCT02925702) examining the effect of germline mutations on outcomes for patients treated with radium-223. Approved based on data from ALSYMPCA, radium-223 is an alpha-emitter that induces double-strand DNA breaks (DSBs) and selectively targets bone metastases. Such DSBs are accurately repaired by the homologous recombination (HR) pathway that is impaired in a significant proportion of mCRPC patients that harbor pathogenic mutations in HR genes (gHR+). Th authors hypothesized that patients with germline mutations in HR genes may have a potentiated response to radium-223.

This analysis is performed in the context of the PRORADIUM (NCT02925702) study, a prospective observational study of mCRPC patients treated with standard-of-care Radium-223.

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Participants were screened for germline mutation in DDR genes using a multigene panel. The authors used alkaline phosphatase (ALP) response at 12 weeks as the primary endpoint. A number of secondary outcomes including PSA response at 12 weeks, time to PSA progression (TTPP), clinical and radiographic progression free survival (cPFS and rPFS) and overall survival (OS) from Ra223 initiation were also analysed.

The authors enrolled a total of 169 patients with mCRPC who were followed for a median of 31 months. The median age at baseline was 73 years (range 45-90) and a performance status ECOG ≤1 was recorded in 85% patients. The median number of prior lines of therapy for mCRPC was 2 (range 0-4), with 63% of patients having previously received at least one taxane.

In terms of treatment, 59.2% of patients received >5 [LA1] cycles of Radium-223. A pathogenic germline HR mutation was identified in 15 (8.8%) pts (5 BRCA2, 4 ATM, 1 BRCA1, 1 CHEK2, 1 BRCA1+CHEK2, 1 BRIP1, 1 NBN, 1 BLM).

A >30% decline in ALP at 12 weeks was observed in 71.4% of patients with germline HR mutations compared to 39.5% of those without germline HR mutations (p=0.022). No differences in PSA >50% decline at 12 weeks or TTPP (2.8 vs 3.0 months, p=0.721) were observed.

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Additionally, median rPFS and cPFS were compared between the two groups: 5.6 vs 6.3 months (p=0.063) and 4.5 vs 6.1 months (p=0.462), respectively. In germline ATM mutated patients rPFS was 6.1 months and cPFS was 6.6 months.

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Further, OS from the initiation of Radium-223 was 16.8 in those with germline HR mutations and 11.5 in those without germline HR mutations (p=0.078). However, for those with germline ATM mutations, OS was 28.7 months (p=0.017).

The authors therefore concluded that germline mutations in HR genes are associated with improved ALP response and a trend towards more prolonged OS, particularly those with gATM mutations.

Presented by: Elena Castro, MD, Medical Oncologist. Clinician Scientist at Spanish National Cancer Research Center, Madrid, Spain

Written by: Christopher J.D. Wallis, University of Toronto Twitter: @WallisCJD during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.

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