What does this research mean for the field?

In a real-world setting, aggressive variant prostate cancer (AVPC) is associated with significantly shorter overall survival and more rapid progression on standard therapies compared to mismatch repair deficient (MMR-d) and biomarker-negative prostate cancer, with a high proportion of both AVPC and MMR-d patients exhibiting concurrent homologous recombination deficiency (HRD). Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to analyze the incidence, characteristics, and outcomes of patients with aggressive variant and mismatch repair deficient prostate cancer.

May 30, 2026

Real-world (RW) characteristics, management, and outcomes of genomically defined mismatch repair deficient (MMR-d) and aggressive variant prostate cancer (AVPC).

Key Points

This research aims to analyze the incidence, characteristics, and outcomes of patients with aggressive variant and mismatch repair deficient prostate cancer.
Prospective multicenter study conducted in Alberta, Canada from 2018-2025.
Patients with AVPC or MMR-d were compared with those not exhibiting any biomarker.
Outcomes such as time to CRPC, overall survival, and treatment responses were assessed using Kaplan-Meier analyses.
Overall survival was shorter for AVPC (11.9 months) compared to MMR-d (13.6 months) and no biomarker detected (37 months), p < 0.01.
Treatment intensification was observed in 97 patients, predominantly involving ARPi therapies.
No impact of concurrent HRD on time to CRPC or overall survival was found for either subtype.

Abstract

e17042 Background: AVPC (≥ 2 alterations in PTEN / TP53 / RB1 ) and MMR-d are genomically distinct subsets of prostate cancer with poor response to androgen-pathway therapies (ARPi) and docetaxel (DTx). Methods: This prospective RW multicenter study (Alberta, Canada) investigates the incidence, characteristics, systemic treatment (tx), and outcomes of pts with metastatic (m) and/or castration resistant prostate cancer (CRPC) receiving genomic testing (2018-2025). Pts with AVPC or MMR-d were compared with pts with no biomarker detected (NBD: lacking AVPC, MMR-d and HRD). Pt characteristics, time to CRPC (tCRPC) from androgen deprivation therapy (ADT) initiation, survival post-mCRPC (OS), time to PSA progression (TTPP), and radiographic PFS (rPFS) were assessed using univariate tests of association and Kaplan-Meier analyses. Results: Of 178 cases, 19 (12%) were AVPC (18 PTEN, 4 RB1, 17 TP53), 19 (12%) MMR-d (4 EPCAM, 3 MLH1, 6 MSH2, 6 MSH6, 2 PMS2), and 140 (76%) NBD. HRD was observed concurrently in 42% (8/19) each of AVPC ATM/PTEN/TP53 (n = 2); BRCA2/PTEN/TP53 (n = 3); BRCA2/TP53/RB1 (n = 2); PALB2/PTEN/TP53 (n = 1); RAD51C/TP53/RB1 (n = 1) and MMR-d ATM/MLH (n = 1); ATM/EPCAM/MSH6 (n = 1); BRCA2/MSH6 (n = 1); BRCA2/MSH2 (n = 2); CDK12/MSH6 (n = 1); CDK12/MSH2 (n = 1); 1 PALB2/MSH6 (n = 1). Excluding concurrent HRD, 11 AVPC (11 PTEN, 2 RB1, 9 TP53), 11 MMR-d (3 EPCAM, 1 MLH1, 2 MSH2, 4 MSH6, 2 PMS2), and 140 NBD were analyzed. Concurrent HRD did not impact tCRPC or OS for AVPC or MMR-d. Clinicopathological features (age, Gleason ≥8, disease volume, visceral or de novo metastases, pathology, PSA) were similar across groups. tCRPC was 16.6, 18.4 and 29.9 mo for AVPC, MMR-d and NBD, respectively (p = 0.6). AVPC had a significantly shorter OS (11.9 mo), compared to MMR-d (13.6 mo) and NBD (37 mo); p < 0.01). 97/178 pts with mCSPC received treatment intensification (66 ARPi 26 APA; 31 ABI; 9 ENZA), 19 ARPi + DTx [8 ABI; 11 DARO, and 12 DTx). 1L mCRPC tx consisted of 82% (41/50) ARPi 2 APA; 20 ABI; 19 ENZA), 16% (8/51) DTx, and 2% (1/50) platinum chemotherapy (P). 2L for mCRPC pts was 77% (39/55) DTx, 24% (13/55) ARPi [6 ABI; 7 ENZA, 3% (2/55) cabazitaxel, and 2% (1/55) P. Conclusions: This RW study identified a high proportion of pts harbouring AVPC or MMR-d were also concurrently HRD. Yet, AVPC is a distinct aggressive subtype with poor outcomes, demonstrating a short OS and tCRPC, and rapid TTPP and rPFS on both ARPi and Dtx. No pts received AKT inhibitors and a single pt with MMR-d (PMS2) received a self-funded immune checkpoint inhibitor, underlining the need for earlier comprehensive biomarker testing in M1 or CRPC and further trial development in these unique subtypes. AVPC n (%) MMR-dn (%) NBDn (%) p 1L Single Agent ARPi N 9/11(81) 8/11 (72) 90/126 (71) 0.3 TTPP 8.3 14.8 26.6 <0.01* R-PFS 8.2 10.3 21.4 <0.01* 2L DTx N 4/7 (57) 5/6 (83) 34/47 (72) 0.8 TTPP 1.4 11.1 10.2 <0.01* R-PFS 4.2 3.0 7.1 0.5

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