Veliparib is a medication being studied as a potential anti-cancer drug. It belongs to a class of targeted therapies called PARP inhibitors. Veliparib aims to enhance the effectiveness of other cancer treatments, such as chemotherapy and radiation, by interfering with cancer cells’ ability to repair their DNA. It is an investigational drug, meaning its use is primarily within clinical trials to determine its safety and efficacy in various cancer types.
How Veliparib Works
Veliparib functions as a poly(ADP-ribose) polymerase (PARP) inhibitor, specifically targeting PARP-1 and PARP-2 enzymes. PARP enzymes are a family of proteins that play a significant role in cellular functions, including the repair of DNA damage. When DNA strands are broken, PARP-1 is activated to initiate the repair process by recruiting other repair proteins.
By inhibiting PARP-1 and PARP-2, veliparib prevents cancer cells from effectively repairing single-strand DNA breaks. These unrepaired single-strand breaks can then accumulate and lead to more severe double-strand breaks. In cancer cells that already have deficiencies in other DNA repair pathways, such as those with mutations in the BRCA1 or BRCA2 genes, inhibiting PARP with veliparib creates a situation known as “synthetic lethality.” This means that while inhibiting either PARP or having a BRCA mutation alone might not be lethal to the cell, the combination of both defects leads to overwhelming DNA damage and ultimately cancer cell death.
Veliparib in Cancer Treatment
Veliparib has been investigated across a range of cancer types, often due to DNA repair defects in these malignancies. Its application involves combination with other therapies that induce DNA damage, rather than as a standalone treatment. This strategy aims to exploit the DNA repair vulnerabilities of cancer cells, making them more susceptible to existing treatments.
A significant area of investigation for veliparib has been in breast cancer, particularly in patients with BRCA1 or BRCA2 gene mutations, which predispose them to developing breast cancer. These mutations impair a DNA repair pathway called homologous recombination, making these cancers more vulnerable to PARP inhibition. Veliparib has also been studied in triple-negative breast cancer (TNBC), a more aggressive subtype that often shares characteristics with BRCA-mutated cancers, even without a direct BRCA mutation.
Ovarian cancer is another malignancy where veliparib has been extensively studied, especially in recurrent cases and those with BRCA mutations. The rationale for its use in ovarian cancer is similar to breast cancer, leveraging existing DNA repair deficiencies. Veliparib has also been explored in non-small cell lung cancer (NSCLC), where it has been observed to enhance the effects of chemotherapy and radiation therapy.
Clinical Trial Outcomes
Clinical trials for veliparib have yielded a mix of outcomes. Early-phase studies demonstrated anti-tumor activity both as a single agent and in combination with standard chemotherapy, particularly in BRCA-mutated breast and ovarian cancers. For instance, a Phase I study in BRCA-positive patients showed an objective response rate of 40% and a clinical benefit rate of 68%. This suggested promising activity in these genetically defined patient populations.
However, larger Phase III trials have presented a more nuanced picture. In 2017, AbbVie, the developer of veliparib, reported that the drug failed to improve outcomes in Phase III trials for both triple-negative breast cancer and squamous non-small cell lung cancer when combined with chemotherapy. These trials did not meet their primary endpoints, indicating a lack of significant benefit in these broader patient groups.
Despite these setbacks, some studies have shown encouraging results in specific subgroups. A systematic review of veliparib trials in lung cancer noted that while most studies found no significant benefit over standard treatment, some indicated improvements in overall survival, progression-free survival, and objective response rate. Additionally, a recent SWOG S1416 clinical trial found that adding veliparib to chemotherapy significantly extended progression-free survival in patients with “BRCA-like” triple-negative breast cancer, a phenotype that mimics BRCA mutations in its DNA repair deficiencies. In this study, patients with “BRCA-like” breast cancer treated with veliparib had a median progression-free survival of 5.9 months compared to 4.2 months in the placebo arm. These findings suggest that patient selection based on specific tumor characteristics or DNA repair deficiencies could be an important factor in veliparib’s efficacy.
Side Effects and Administration
Veliparib is administered as an oral capsule. Like many cancer treatments, it can cause side effects, which have been observed in clinical trials. The most commonly reported adverse events include nausea and fatigue.
Other side effects can include vomiting and anemia. More severe, though less frequent, side effects can involve changes in blood cell counts. Severe nausea and fatigue have been reported, and rare cases of seizure have occurred at higher doses. While side effects can lead to dose reductions or treatment discontinuation in some patients, veliparib has been considered to have an acceptable toxicity profile when used alone or in combination with chemotherapy.