BRCA Reversion Mutations in Patients With Metastatic Castration-Resistant Prostate Cancer After Treatment With Rucaparib

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In this post hoc analysis of TRITON2, the authors collected cell-free DNA (cfDNA) samples of 100 BRCA-mutated patients with mCRPC who had progressed on rucaparib to evaluate BRCA reversion mutations as a mechanism of acquired resistance to PARP inhibitors. Among the 100 patients included in the analysis, 39 had BRCA reversion mutations. None of them had a pretreatment BRCA reversion mutation. The rates of reversion mutations were similar in BRCA1 and BRCA2. As the treatment duration increased, so did the incidence of reversion mutations. There were more detectable reversion mutations among patients with PSA responses than among those without PSA responses.

This study suggests that BRCA reversion mutations are an important mechanism underlying resistance to PARP inhibitors.

– Vinay Mathew Thomas, MD

Abstract

This abstract is available on the publisher's site.

BACKGROUND

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown.

OBJECTIVE

To examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib.

DESIGN, SETTING, AND PARTICIPANTS

Men with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS).

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

The association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib.

RESULTS AND LIMITATIONS

No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively).

CONCLUSIONS

These findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance.

PATIENT SUMMARY

Men with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations.

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Additional Info

Article Citation

European Urology

Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib

Eur Urol 2022 Oct 12;[EPub Ahead of Print], A Loehr, A Hussain, A Patnaik, AH Bryce, D Castellano, A Font, J Shapiro, J Zhang, B Sautois, NJ Vogelzang, G Chatta, K Courtney, A Harzstark, F Ricci, D Despain, S Watkins, C King, M Nguyen, AD Simmons, S Chowdhury, W Abida

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.