(UroToday.com) The 2023 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. Steven Yip discussing germline vs somatic origin of Homologous Recombination Repair (HRR) gene alterations and potential associations with antitumor activity in the HRR-deficient population from TALAPRO-2.
TALAPRO-2 evaluated the PARP inhibitor talazoparib combined with the androgen receptor pathway inhibitor enzalutamide as first line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC).1 The primary endpoint was radiographic PFS (rPFS) assessed centrally. Exploratory biomarker analyses assessed germline versus somatic origin of HRR gene alterations and potential associations with efficacy in the HRR-deficient population from TALAPRO-2.
Alterations were defined as known/likely pathogenic variants. The frequency of germline HRR alterations was assessed in patients evaluable for saliva sequencing using the Ambry CustomNext-Cancer panel (sequenced 9/12 genes from the HRR12 tumor panel). Association of germline versus somatic tumor HRR mutation and efficacy was assessed in the ITT population using saliva data (or solid tumors germline zygosity prediction when adequate saliva results are unavailable) to annotate tumor alteration origin (limited to short variants). Associations with rPFS were evaluated using a stratified log-rank test, and the data cutoff used was October 3, 2022.
Among the 302 patients evaluable for germline HRR alterations, 91 patients (30.1%) exhibited ≥1 HRR alteration in their saliva: BRCA2 (14.9%), CHEK2 (7.3%), ATM (4.0%), PALB2 (2.3%), BRCA1 (1.0%), NBN (1.0%), MRE11A (0.7%), and MLH1 (0.3%):
Where evaluable, solid tumor and prospectively tested baseline ctDNA HRR alterations were typical somatic origin (ie. BRCA2 [44 germline vs 50 somatic], CDK12 [1 germline vs 27 somatic], ATM [14 germline vs 49 somatic]) with some exceptions (ie. BRCA1 [7 germline vs 4 somatic], CHEK2 [24 germline vs 2 somatic], NBN [5 germline vs 2 somatic]):
rPFS was comparable for patients with germline and somatic alterations in the talazoparib + enzalutamide arm (HR 0.69, 95% CI, 0.36–1.34; 2-sided p = 0.44), but relatively shorter for germline HRR alterations patients in the placebo + enzalutamide arm (HR 2.27, 95% CI, 1.32 –3.91; p = 0.03).
Dr. Yip concluded his presentation discussing germline vs somatic origin of HRR gene alterations and potential associations with antitumor activity in the HRR-deficient population from TALAPRO-2 with the following concluding statements:
- Germline HRR mutation incidence in mCRPC patients with tumor HRR mutation was 30.1% in the TALAPRO-2 trial
- There was no association with differential antitumor activity for talazoparib + enzalutamide was observed in tumors bearing HRR mutation of germline vs somatic origin
- Though the analyses were exploratory, a shorter rPFS in placebo + enzalutamide-treated germline HRR alterations patients may reflect an intrinsically poor prognosis subgroup that could be prioritized for talazoparib + enzalutamide treatment
- These results warrant further study
Presented by: Steven M. Yip, MD, MSc, Tom Baker Cancer Centre, Calgary, Alberta, Canada
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.
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