ESMO Congress 2026

The evidence base for selecting treatment by genomic alterations in mCRPC rests on tissue sequencing. ^[1] performed prospective whole-exome and transcriptome sequencing of bone or soft-tissue metastases from 150 mCRPC patients, finding BRCA2, BRCA1 and ATM aberrations at 19.3% overall, substantially higher than in primary prostate cancer, with 89% of patients harboring clinically actionable aberrations — establishing a tumor-tissue-driven precision framework. ^[2] subsequently linked genomics to longitudinal outcomes in 429 mCRPC patients: among 128 treated with a first-line ARSI (abiraterone or enzalutamide), only RB1 alteration was significantly associated with poor survival, while RB1, AR and TP53 alterations were associated with shorter time on ARSI; ^[5], in 202 prospectively biopsied mCRPC patients, showed that DNA repair pathway alterations were nearly mutually exclusive with treatment-emergent small-cell neuroendocrine prostate cancer (P=.035). Together these show that tissue-level genomic stratification is well established, and that abiraterone, enzalutamide and other agents have guideline-supported roles in CRPC ^[3], providing the backdrop for this meeting's reports.

Three mCRPC items emerged from ESMO 2026 (#ESMO26), with the main line being the origin of HRR alterations detected by liquid biopsy. The analysis presented by @EAntonarakis (@UMNCancer) showed that 56% of HRR alterations detected by liquid biopsy were predicted to originate from clonal hematopoiesis (CH); patients with CH-only HRR alterations did not appear to benefit from PARPi monotherapy, and the presenter stressed that distinguishing CH from tumor-derived mutations is critical for treatment selection. Two other reports: @quimmateo (VHIO) presented Himalayas-1, a global Phase 3 study of rinzimetostat, an allosteric PRC2 inhibitor, combined with darolutamide in mCRPC patients previously treated with abiraterone acetate; and Dr. Ann-Britt Jones presented results of the BARCODE2 trial of targeted treatment based on genetic profiling. Written coverage of all three by @zklaassen_md on UroToday.

Relative to prior knowledge, this readout moves the question from 'what alterations are in the tissue' to 'whether alterations detected in plasma are tumor-derived'. The actionable catalog of ^[1] was built on metastatic tissue biopsies, whereas routine practice relies heavily on liquid biopsy; the 56% figure suggests that a substantial fraction of HRR positives detected in ctDNA may not be tumor-derived, and using PARPi monotherapy without such discrimination may enroll inappropriate patients. The signal that CH-only patients did not appear to benefit adds a quality-control step to defining the PARPi-eligible population, and implies that HRR-positive populations in future reports should be interpreted with variant origin taken into account.

The limitations are equally clear: the posts disclose neither the sample size, the CH prediction method, nor specific PARPi efficacy figures for this analysis, and the 'no benefit' finding remains at the level of 'appeared to'; efficacy and safety data from Himalayas-1 and detailed BARCODE2 results are not given in the posts, with those numbers to be confirmed in the written coverage and full abstracts.