JCO Precision Oncology Conversations

In this JCO Precision Oncology Article Insights episode, Mitchell Elliot summarizes the article “Talazoparib in Patients With Solid Tumors With BRCA1/2 Mutation: Results From the Targeted Agent and Profiling Utilization Registry Study” by Dr. Jordan Srkalovic et al. published on June 12th, 2024.

TRANSCRIPT

Mitchell Elliott: Hello, welcome to JCO Precision Oncology Article Insights. I'm your host Mitchell Elliott, an ASCO Journals Editorial Fellow. Today I'll be providing a summary of the article titled, “Talazoparib in Patients With Solid Tumors With BRCA1/ 2 Mutation: Results From the Targeted Agent and Profiling Utilization Registry Study,” by Dr. Jordan Srkalovic et al.

The Targeted Agent and Profiling Utilization Registry Study is a phase 2 basket trial evaluating the anti-tumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with various solid tumors with germline or somatic BRCA1 and 2 mutations treated with talazoparib are reported. BRCA1 is involved in both non homologous end joining, and homologous recombination, while BRCA2 primarily facilitates homologous recombination. These mutations are present in a range of cancers including breast, ovarian and pancreatic cancers, making them key targets for therapies that inhibit poly (ADP-ribose) polymerase or PARP, a family of proteins critical for DNA repair. PARP inhibitors like talazoparib have shown promise in treating cancers with BRCA mutations as they prevent tumors from repairing DNA damage, thus promoting cell death. Many PARP inhibitors are standard of care in both early and advanced cancers.

Talazoparib was previously FDA approved for BRCA related HER2 negative breast cancer and prostate cancer. The TAPUR study aims to investigate the effectiveness of talazoparib and other types of solid tumors with BRCA1 and 2 mutations to expand its potential therapeutic applications. Eligible patients had to meet both general and drug specific criteria for inclusion in the study. General eligibility required participants to have advanced or metastatic solid tumors measurable by the RECIST version 1.1 criteria, a performance status of 0 to 2 based on the Eastern Cooperative Oncology Group Scale, and a genomic target identified through certified laboratory testing. Patients with germline or somatic BRCA1 or 2 mutations were eligible, but the genomic test did not always differentiate between these types of mutations. Additional criteria included being age 18 years or older, using effective contraception and avoiding sperm donation at the set period. Exclusion criteria included patients with HER2 negative breast cancer, prior PARP inhibitor treatments, or certain cardiovascular conditions. The study also excluded patients with recent major surgeries, coagulopathy and serious medical conditions, but there were no criteria related to prior platinum therapies. Patients received 1 milligram of talazoparib daily until disease progression, unacceptable toxicity, or other reasons for discontinuation.

The primary endpoint of the study was disease control which was defined by achieving either objective response or stable disease lasting at least 16 weeks as assessed by the RECIST criteria. Secondary endpoints included objective response, progression free survival, overall survival, duration of response, duration of stable disease, and safety. The study enrolled 28 eligible patients with 20 different solid tumors that had BRCA1/2 alterations between December 2019 and September 2021 across 19 clinical sites with most patients, about 89%, enrolled from community-based locations in the United States. The most common tumor type was non-small cell lung cancer accounting for 18% of cases. All patients were included in both the safety and efficacy analyses including three with HER2 negative breast cancer and somatic BRCA alterations. Of the 28 patients, nine had tumors with BRCA1 alterations, 16 had BRCA2 alterations and three had both BRCA1 and BRCA2 alterations. Additionally, 64% of patients had tumors with coalterations and at least one DNA damage repair gene.

In the study, one patient achieved a complete response, nine patients had partial response and six patients had stable disease for at least 16 weeks. The overall disease control rate was 57% with an objective response of 36%. The study rejected the null hypothesis of a 15% disease control rate with high statistical significance with a p-value of less than 0.001. The median progression free survival was 24 weeks and median overall survival was 71 weeks. Interestingly, among the 19 patients who received prior platinum-based chemotherapy, 5, or about 26%, had a partial response and 4 had stable disease while on talazoparib. While platinum therapy exposure can be associated with BRCA reversion mutations, it is notable that these patients achieve stable disease with PARP inhibitor treatment. 46% of the 28 patients experienced grade 3 - 5 adverse events or serious adverse events that were possibly related to talazoparib. 14% of patients had possible drug related serious adverse events which included conditions such as anemia, neutropenia, leukopenia, nausea and vomiting. More severe grade 4 or 5 events included anemia, neutropenia, thrombocytopenia, leukopenia, hyponatremia, and increased level of the aspartate aminotransferase and bilirubin.

In conclusion, this study demonstrates that talazoparib shows significant antitumor activity in patients with advanced solid tumors carrying both BRCA1 and BRCA2 mutations, even in cancers beyond those for which PARP inhibitors are currently FDA approved. The disease control and objective response rates indicate promising results in heavily pretreated patients who have no standard treatment options left. The findings suggest that PARP inhibitors like telazoparib could be effective in a broad range of cancers, including non-small cell lung cancer, mesothelioma and hepatocellular carcinoma where PARP inhibitors are not yet approved. This could pave the way for expanding the use of these drugs in precision oncology. While talazoparib showed efficacy, the study also reported a notable incidence of grade 3 to 5 adverse events, highlighting the need for careful management of side effects, particularly in heavily pretreated patients. The study calls for further research, particularly in randomized controlled trials to confirm the efficacy of talazoparib in other cancers beyond what is currently approved. It also suggests investigating the effect of DNA damage repair gene alterations and exploring combinations of PARP inhibitors with other targeted therapies. Additionally, further studies are needed to understand the potential differences in response between BRCA1 and BRCA2 mutations.

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