Highlights: A meta-analysis of the efficacy of cancer drugs

German researchers compare the therapeutic value of PARP inhibitors in the management of ovarian cancer

By R.N. Sugitha Nadarajah

Poly (ADP-ribose) polymerase


oly (ADP-ribose) polymerase (PARP) inhibitors are significantly effective in the management of ovarian cancer in patients, according to a meta-analysis research conducted by two researchers hailing from Germany.

PARP inhibitor is a substance that blocks an enzyme in cells called PARP which helps repair DNA when it becomes damaged, according to the National Cancer Institute (NCI).

“This study investigated clinical trials of PARP inhibitors, in order to obtain a more complete prognosis of ovarian cancer patients, which is usually dependent on their BRCA1/2 mutation status,” reported Dr. Ines Vasconcelos from Berlin Oncological Centre and her colleague Oscar Gaspar, from Oberlin Clinic, Germany, in a recent article published by the journal Advances in Modern Oncology Research (AMOR).

BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins which help repair damaged DNA and thus ensure the stability of the cell’s genetic material, according to NCI. When any one of these genes is mutated, it is either unable to produce the tumor suppressor proteins or the protein produced does not function properly.

In general, BRCA1/2-defective ovarian cancer cells are unable to properly perform DNA repair through the homologous recombination pathway. “This defectiveness provides more error-prone DNA repair mechanisms that lead to genetic abnormalities and genetic instability of the cancer cells,” said the researchers.
PARP inhibitors help to block these more error-prone mechanisms of DNA repair, which then cause the death of cancer cells, the researchers explained.

PARP pullquote

According to their paper, PARP inhibitors are FDA-approved as monotherapy for patients who were previously treated with three or more lines of chemotherapy.

“PARP-inhibitors are definitely causing a paradigm shift in the way BRCA-mutation-related ovarian cancer is being treated,” noted Dr. Ines Vasconcelos and her fellow researcher.

“PARP-inhibitor development and introduction into the clinical trial phase was initially hampered by a negative trial outcome with inaparib, a drug that is no longer considered as PARP-inhibitor,” they said.

Nevertheless, PARP inhibitors are the only novel drugs approved for ovarian cancer since 2006, according to the researchers. It is important to also note that PARP inhibitors – such as veliparib, olaparib, niraparib and a few others – are currently only approved for patients with an underlying BRCA1/2 germline mutation.

ORR comparisons

Dr. Vasconcelos and her teammate carried out an extensive meta-analysis using PubMed database search with the aim of determining the overall response rate (ORR) in patients with recurrent high-grade serous ovarian cancer by investigating the available clinical trials that utilize PARP inhibitors for these patients.

They also conducted a sub-analysis to see whether patients particularly with wild-type (i.e. normal) BRCA1/2 would benefit from being treated with the PARP inhibitors.

The researchers’ analysis technique involved searching the PubMed database using key terms ‘PARP inhibitor’, ‘olaparib’, ‘veliparib’, ‘niraparib’, or ‘rucaparib’, and ‘ovarian cancer or solid tumor’, while narrowing the article type selection to clinical trials only. They retrieved the titles, abstracts and also the full texts of potentially relevant articles and examined them thoroughly.

In this analysis, 1,042 patients with either high-grade serous ovarian, fallopian tube or primary peritoneal were included, where 587 of them either had a BRCA1or BRCA2 germline mutation and 370 of them were platinum-sensitive, i.e., their ovarian cancer recurs more than six months after completing primary therapy with a platinum-based medication.

“Two of the studies evaluated the use of veliparib, eight evaluated the use of olaparib, and one evaluated the use of niraparib,” explained the researchers. It is important to note that owing to the low outcome numbers of other PARP inhibitor studies, only the ORR for olaparib monotherapy was pooled, thereby precluding statistical analysis.

PARP pullquote 2

“The final results obtained from the analysis showed that the overall response rate for patients who underwent treatment with olaparib was 44.5%,” the researchers reported. In comparison, results with veliparib were observed to be less encouraging, with ORRs of 14.8%–26.0%.

“Olaparib proved to be a highly active drug in ovarian cancer, an otherwise virtually untreatable disease,” their meta-analysis revealed.

According to the paper, the evaluation of the primary endpoint for the BRCA1/2germline mutation status was based on the ORR analysis from five available clinical trials, and the results showed that the pooled ORR for BRCA1/2 germline mutation carriers and wild-type BRCA1/2 patients were 56.6% and 57.9%, respectively.

“There was no significant difference in the ORR between patients havingBRCA1/2 germline mutation and those with wild-type BRCA1/2 gene,” the researchers commented.

Effective treatment

Dr. Vasconcelos and her colleague raised a number of crucial points, one of which is that although PARP inhibitors are traditionally seen as the drug of choice for treating BRCA-mutated high-grade serous ovarian carcinoma, their analysis revealed that there was no significant difference in the pooled ORR between patients having BRCA1/2 mutation and wild type BRCA1/2 gene.

This fact raised concerns that ovarian cancer patients, who might potentially benefit from this form of therapy, are currently being excluded from this treatment option.

Another important point refers to the apparent synergistic activity with cediranib, according to the researchers. A phase II clinical trial which evaluated the combination treatment of cediranib with olaparib reported an almost 80% ORR and nearly 18 months progression-free survival (PFS).

“These are unprecedented exceptional results that should be pointed out in the correct therapeutic direction, with cediranib drug being incorporated in future trials,” the research team recommended. “Bevacizumab, a successful drug used in advanced ovarian cancer, could also be of potential interest and should be evaluated in this analysis setting,” they added.

In a separate exclusive interview with AMOR media team, Dr. Vasconcelos reasserted, “PARP-inhibitors have been established as valid therapeutic options and have shown a synergistic action with anti-angiogenic agents through changes in oxygenation.”

In addition, Dr. Vasconcelos emphasized on the importance of meta-analysis in the field of medical research which proved beneficial in the study.

“Meta-analysis offers a powerful tool to cumulate and summarize the knowledge in this field and to identify the overall treatment effect by combining several conclusions,” she told AMOR.

The subsequent meta-analysis that was carried out by Dr. Vasconcelos and her colleague led to the conclusion that PARP inhibitors, specifically olaparib, proved to be effective in managing BRCA1/2 germline-mutated ovarian cancer.

“Nonetheless, fine-tuning is still necessary to identify patients with wild-typeBRCA1/2 genes and other forms of BRCAness or BRCA-independent homologous recombination-deficient tumors, who may respond to therapy with olaparib,” the researchers reported. They further added, “Equal importance should be given to the rational development of combinatory treatment involving chemotherapy and PARP inhibition.”