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Authors Sarina A. Piha-Paul, Wendy Wen Xiong, Tyler Moss, Rosa M. Mostorino, Shelby Sedelmeier, Kenneth Hess, Siqing Fu, David Hong, Filip Janku, Daniel Karp, Aung Naing, Shubham Pant, Jordi Rodon, Vivek Subbiah, A M. Tsimberidou, Timothy Yap, Milind Javle, Coya Tapia, Kenna R. Shaw, Karina Eterovic, Gordon B. Mills and Funda Meric-Bernstam
Title Abstract A096: Phase II study of the PARP inhibitor talazoparib in advanced cancer patients with somatic alterations in BRCA1/2, mutations/deletions in PTEN or PTEN loss, aberrations in other BRCA pathway genes, and germline mutations in BRCA1/2 (not breast or ovarian cancer)
Journal Mol Cancer Ther
Vol 17
Issue 1 Suppl
Date 2018
URL https://mct.aacrjournals.org/content/17/1_Supplement/A096
Abstract Text Background: Cancer cells deficient in BRCA1/2 are selectively sensitive to the double-stranded DNA breaks induced by poly (ADP-ribose) polymerase (PARP) inhibitors. Multiple ongoing trials are evaluating PARP inhibitors in patients with breast, ovarian, and prostate cancers and germline or somatic BRCA1/2 mutations. There is, however, a great need to determine if the benefit of PARP inhibition can be extended to other tumor types. We sought to assess the efficacy of talazoparib, a potent oral PARP1/2 inhibitor, in patients with germline BRCA mutations in cancer types other than breast and ovarian cancer, and in patients with somatic BRCA alterations or aberrations in other homologous repair genes or PTEN. Methods: This was a single-center, phase II trial in patients with measurable advanced solid tumors. Patients were enrolled on one of four cohorts: 1) somatic alterations of BRCA1/2, 2) mutations/deletions in other BRCA pathway genes, 3) mutations/deletions in PTEN and/or PTEN loss by IHC, and 4) germline BRCA1/2 mutations (not breast/ovarian cancer). Patients were treated with talazoparib at 1 mg PO daily. Response was assessed per RECIST v1.1. Primary end point was clinical benefit rate (CBR; complete response [CR], partial response [PR] or stable disease [SD]>6m). Patients were enrolled based on standard of practice molecular testing. Patients underwent pretreatment biopsies with whole exome sequencing (WES) of tumor and normal DNA. Results: 35 patients (pts) (30 evaluable) were enrolled. Pts had a median of 4 prior lines of treatment. Grade 3-4 treatment-related AEs occurred in 37% of pts, and the most common was thrombocytopenia (23%). The median follow-up was 15.8 mo. CBR was 0%, 44%, 8%, and 29% for cohorts 1-4, respectively. In cohort 1, one patient with a somatic BRCA2 mutation enrolled and did not respond. In cohort 2, two of 9 evaluable pts had a PR: cholangiocarcinoma [CCA] with ATM mutation and bladder cancer with PALB2 mutation, and 2 of 9 pts had prolonged SD (one pt with ovarian cancer and BRIP1 mutation, and one pt with sarcoma and FANCC mutation). Among 13 evaluable pts in the PTEN mutation/loss cohort (cohort 3), one patient with PTEN mutation had prolonged SD. Among 7 evaluable pts with germline BRCA1/2 mutations (cohort 4), one pt with carcinoma of ampulla of Vater had a durable CR, and one pt with CCA had SD for 8 months. WES was performed on 28 evaluable patients. Alterations in two genes, POLQ and PTEN, were significantly associated with progressive disease. PTEN mutations were associated with shorter time to progression (p=0.004) and lower overall survival (p=0.02). Conclusion: Talazoparib demonstrated clinical benefit in selected patients with germline as well as somatic alterations in BRCA pathway genes. Patients with PTEN mutations/loss did not derive significant clinical benefit from PARP inhibition. Further study is needed to confirm these findings and determine implications for patient selection and combination therapy. Clinical trial information: NCT 02286687.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN mutant Advanced Solid Tumor no benefit Talazoparib Phase II Actionable In a Phase II trial, Talzenna (talazoparib) treatment did not result in significant clinical benefit in patients with advanced solid tumors harboring PTEN mutation or loss (by IHC), with one patient harboring a PTEN mutation achieved a prolonged stable disease as best response in a cohort of 13 patients (Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A096; NCT02286687). detail...
PTEN negative Advanced Solid Tumor conflicting Talazoparib Phase II Actionable In a Phase II trial, Talzenna (talazoparib) treatment did not result in significant clinical benefit in patients with advanced solid tumors harboring PTEN mutation or loss (by IHC), with one patient harboring a PTEN mutation achieved a prolonged stable disease as best response in a cohort of 13 patients (Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A096; NCT02286687). detail...