The time has come to offer all patients a PARP [poly (ADP-ribose) polymerase] inhibitor,” said Mansoor R. Mirza, MD, Chief Oncologist at Copenhagen University Hospital and the invited discussant of the VELIA trial at the ESMO Presidential Symposium. He noted, however, that he wasn’t sure veliparib plus chemotherapy followed by maintenance is the optimal choice.

Mansoor R. Mirza, MD

VELIA was the first phase III study to assess the impact of combination chemotherapy plus a PARP inhibitor followed by maintenance with the PARP inhibitor. It differed from the other phase III PARP inhibitor trials in advanced ovarian cancer presented at ESMO—PAOLA-1 and PRIMA—in several ways, Dr. Mirza said, and they should be noted when interpreting the findings:

• In VELIA, patients were randomly assigned at the start of chemotherapy; thus, progression-free survival was measured from the time chemotherapy was initiated, rather than from the time it was completed.
• In VELIA, patients were stratified by germline BRCA status, somatic BRCA status, or no BRCA status, rather than homologous recombination deficiency status.
• In VELIA, subjects who completed combination therapy and had not had disease progression received single-agent veliparib, meaning that maintenance veliparib was evaluated not only in responders but in patients with stable disease.

The above points bring the VELIA trial population closer to the real-world population. Other interesting characteristics of VELIA, in Dr. Mirza’s opinion, included that two-thirds of the patients had primary debulking surgery, two-thirds had no gross residual disease, and two-thirds were homologous recombination deficiency–positive, perhaps because the cutoff for homologous recombination deficiency score in this study was not 42, but 33.

Outstanding Questions

VELIA demonstrated activity in patients with BRCA mutations and in the overall intent-to-treat population, but Dr. Mirza posed questions about the findings. “The stratification was according to BRCA mutation status and the study was powered to show the benefit in the population with BRCA mutations; however, the statistical design was not powered to evaluate the efficacy of veliparib in the BRCA wild-type population. Thus, one can speculate that the effect in the overall population might be driven by patients in the BRCA-mutation subgroup,” he said.

To understand the efficacy of veliparib in the BRCA wild-type population, he continued, “one needs to depend upon the exploratory/secondary analysis, but the study is underpowered for such an analysis. The hazard ratio in the BRCA wild-type population is 0.81, and confidence intervals cross the boundary of 1.0. As the trial is underpowered for evaluating efficacy, it is difficult to conclude whether this finding is really nonsignificant or a statistical weakness. However, a hazard ratio of 0.81 has no clinical significance, as other treatments have demonstrated greater efficacy. The same is the case for other subgroups of the BRCA wild-type population. None of these findings have clinical significance. Payers will therefore argue against the use of veliparib in the BRCA wild-type population, especially in lieu of results of other PARP inhibitor trials and the question of whether veliparib’s benefit is restricted to patients with the BRCA mutation.”

Second, is there a benefit to adding veliparib to chemotherapy? No progression-free survival benefit was achieved by adding veliparib to chemotherapy, vs chemotherapy alone, in patients who did not also undergo maintenance with the drug. Grade 3 or 4 toxicity, however, was increased with veliparib as part of induction. Third, how does one interpret the results in the veliparib-throughout arm, without having a pure maintenance arm for comparison? “In the absence of a study arm that assesses veliparib as maintenance alone, we don’t know if giving veliparib with chemotherapy is necessary for the observed activity,” he said.

Dr. Mirza’s conclusion was that the addition of veliparib to chemotherapy did not provide a benefit over what is observed in other first-line PARP inhibitor trials. The absence of a comparator arm with veliparib included only for maintenance “makes it unclear if the addition of veliparib to chemotherapy is necessary to provide the observed benefit.” 

DISCLOSURE: Dr. Mirza has financial relationships with AstraZeneca, Biocad, Boehringer Ingelheim, Clovis Oncology, Geneos, Genmab, Karyopharm Therapeutics, Merck, Oncology Venture, Pfizer, Roche, Seattle Genetics, Sera Prognostics, Sotio, Tesaro-GSK, and Zai Lab and has a leadership role with Karyopharm Therapeutics and Sera Prognostics.