ESMO 2021: TALAPRO-1: Talazoparib Monotherapy in Metastatic Castration-Resistant Prostate Cancer With DNA Damage Response Alterations—Exploration of Non-DDR Mutational Landscape and Potential Associations With Antitumor Activity

(UroToday.com) In the on-demand poster session of the European Society for Medical Oncology (ESMO) Annual Congress, Niven Mehra presented an exploratory ad hoc biomarker analyses assessing non-DDR/HRR mutational landscape and associations with antitumor activity among patients treated with talazoparib for metastatic castration-resistant prostate cancer (mCRPC) in the TALAPRO-1 trial (NCT03148795).

This trial enrolled men with progressive mCRPC and an 11-gene panel assessing tumor DNA Damage Response Alterations (DDRm) involved either directly or indirectly in homologous recombination repair (HRR). In the context of the trial, included men had received 1–2 taxane-based chemotherapy and progressed on ≥1 novel hormonal therapy before inclusion. The primary study endpoint was objective response rate ([ORR] per RECIST v.1.1; central review).

In this exploratory biomarker-based analysis, tumor alteration prevalence was assessed in the enrolled population for whom FoundationOne CDx® data were evaluable (n=123). Alterations were defined as known/likely pathogenic variants. Potential associations between alteration status of selected genes and antitumor activity were explored in the HRR-deficient measurable disease population evaluable for FoundationOne CDx® (n=100).

Among the 123 evaluable patients, the most commonly altered non-HRR genes (prevalence ≥10%) were TMPRSS2, its fusion partner ERG, TP53, and PTEN when copy number alterations (CNAs) were excluded. The most common non-HRR CNAs (prevalence ≥9%) were PTEN, androgen receptor (AR), and MYC. Based on their importance in CRPC pathobiology and crosstalk potential with DDR/HRR pathways, associations between alteration status of TP53, PTEN, AR, or MYC and antitumor activity were explored. As of a data cut-off of 4 Sept 2020, the ORR was 30.0% (9/30) in men with TP53m and 28.6% (20/70) in men without TP53m (P = 1.00, 2-sided Fisher’s exact test). ORR was 34.5% (10/29) in men with PTENm and 26.8% (19/71) in men without PTENm (P = 0.47). ORR was independent of AR or MYC alteration status. There was no significant difference in radiographic PFS based on the alteration status of these 4 genes.

Mehra - ESMO21 - Figure1 

The authors conclude that these results demonstrate that the alteration status of non-HRR genes does not appear to be associated with antitumor activity, within the context of men selected for therapy on the basis of HRR alteration.

Presented by: Niven Mehra, MD, Ph.D. Radbourd University Medical Center, Nijmegen, Surrey, Netherlands