gLOH-High May Be a Marker for Improved Response to Talazoparib in mCRPC

Johann de Bono, MB, ChB, FRCP, MSc, PhD, FMedSci

In patients with metastatic castration-resistant prostate cancer (mCRPC), high genomic loss of heterozygosity (gLOH) scores may serve as a predictive marker for response to treatment with talazoparib (Talzenna), according to an analysis of the phase 2 TALAPRO-1 (NCT03148795) trial presented at the AACR Annual Meeting 2022.¹

In this post-hoc exploratory analysis, 2 thresholds were used to evaluate gLOH-high and gLOH-low status: 8.8%, based on literature showing this cutoff was optimally distinguished from prostate cancers bearing BRCA bialletic alterations from BRCA wild-type, and 9.2%, based on the median gLOH score in TALAPRO-1 in the gLOH-evaluable population. A total of 55 patients were included in this study.

The objective response rate with talazoparib among 30 patients with gLOH-high status at the 8.8% cutoff was 53.3% (95% CI, 34.3%-71.7%) vs 12.0% (95% CI, 2.5%-31.2%) for those with gLOH-low status (n = 25; odds ratio [OR], 8.38; 95% CI, 1.83-51.0; 2-sided P = .0017). The complete response (CR) rate was 10% vs 4%, respectively, and the partial response (PR) rate was 43.3% vs 8.0%, respectively.

In an analysis of patients using the 9.2% threshold, among the 28 patients with gLOH-high status, the ORR was 53.6% (95% CI, 33.9%-72.5%) vs 14.8% (95% CI, 4.2%-33.7%) for the 27 patients with gLOH-low status (OR, 6.64; 95% CI, 1.60-32.2; 2-sided P = .0041). The CR rates were 7.1% vs 7.4%, respectively, and the PR rates were 46.4% vs 7.4%, respectively.

gLOH scores are relatively low in prostate cancer and do not exhibit the dynamic range seen in breast and ovarian cancers. However, study author Johann de Bono, MB, ChB, FRCP, MSc, PhD, FMedSci, who is an honorary consultant in medical oncology, a professor in experimental cancer medicine, and director of The Drug Development Unit at The Institute of Cancer Research and Royal Marsden in London, notes that these findings suggest gLOH status is worthy of study in a larger patient population as a predictive biomarker.

“Based on these retrospective ad hoc exploratory analyses, gLOH-high status seems to associate with a higher enhanced response to talazoparib…in men with heavily pretreated mCRPC,” he said.

Investigators have previously shown that biallelic alterations in DNA damage response (DDR)/homologous recombination repair (HRR) genes are associated with increased response across several solid tumors that may benefit from treatment with PARP inhibitors. High gLOH is a known marker of sensitivity to platinum-based chemotherapy and PARP inhibitors.¹

de Bono said it is likely that patients with BRCA2 mutations are driving the gLOH data compared with those who have ATM mutations. Not surprisingly, patients with BRCA mutations were more likely to display a positive ORR compared with ATM at both high and low gLOH scores.

Specifically, using the 8.8% threshold, 17 patients had gLOH-high status and 13 patients had gLOH-low status and a BRCA2 mutation. The ORR was 70.6% (95% CI, 44.0%-89.7%) vs 23.1% (95% CI, 5.0%-53.8%), respectively (OR, 8.0; 95% CI, 1.23-61.0; 2-sided P = .0253). The CR and PR rates were 11.8% and 58.8% for those with gLOH-high status, and were 7.7% and 15.4% for those with gLOH-low status.

In terms of ATM-mutant disease, 4 patients had gLOH-high status and 6 patients had gLOH status. The ORR was 50% (95% CI, 6.8%-93.2%) vs 0% (95% CI, 0%-45.9%), respectively. One patient had a CR, and 1 patient had a PR following treatment with talazoparib in the gLOH-high cohort compared with no patients experiencing a response in the gLOH cohort.

gLOH status did not translate into longer radiologic progression-free survival (rPFS). At the 8.8% threshold, the median rPFS was 10.9 months (95% CI, 7.5-not evaluable) in the gLOH-high group (n = 30) compared with 11.1 months (95% CI, 2.1-19.2) in the gLOH-low group (n = 25).

“The gLOH cut-off did not define patients who were staying on PARP inhibition [the] longest,” de Bono said. “The Kaplan Meier plot shows gLOH-high and -low [status] was not significantly different and did not separate significantly in this analysis.”

The analysis follows the published findings of the TALAPRO-1 trial, in which heavily pretreated patients with mCRPC received at least 1 dose of 1 mg daily oral talazoparib at 43 medical facilities around the globe. Patients were previously treated with at least 1 taxane-based chemotherapy, as well as abiraterone acetate (Zytiga)/prednisone, enzalutamide (Xtandi), or both hormonal agents.

All patients had at least 1 HHR gene alteration from a panel of 11 genes likely to sensitize their tumor to PARP inhibition: ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C.

At a median follow-up of 16.4 months (interquartile range, 11.1-22.1), the ORR was 29.8% (95% CI, 21.2%-39.6%) among 104 evaluable patients. Antitumor effects were most notable in patients with BRCA1/2 mutations, with a confirmed ORR of 45.9% and a median rPFS of 11.2 months.²

In the safety analysis of 127 patients, the most common grade 3/4 treatment-emergent adverse events (TEAEs) were anemia (31%), thrombocytopenia (9%), and neutropenia (8%). Investigators observed serious TEAEs in 34% of patients. There were no treatment-related deaths.²

_References

_{1. de Bono JS, Mehra N, Laird D, et al. TALPRO-1: talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)-exploration of genomic loss of heterzygosity (gLOH) and potential association with antitumor activity. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT031. Accessed April 11, 2022. https://www.abstractsonline.com/pp8/#!/10517/presentation/20169}

_{2. de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250-1264. doi:10.1016/S1470-2045(21)00376-4}