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TAMPA, Fla. -- Advanced ovarian cancer treated with PARP (poly-ADP ribose polymerase) inhibitor maintenance therapy had significant improvement in progression-free survival (PFS), extending beyond first progression, investigators reported.

Patients randomized to olaparib had a 60% improvement in the exploratory endpoint of time to first subsequent therapy or death (TFST) as compared with placebo-treated patients, according to Ursula Matulonis, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues. Time to second subsequent therapy (TSST) also was significantly prolonged in the olaparib group.

The significant advantage applied to the overall analysis and to subgroup analyses by BRCA mutation status, they reported here at the Society of Gynecologic Oncology meeting.

"In this phase II trial, olaparib maintenance monotherapy led to clinical benefits that persisted beyond the first progression by RECIST criteria," Matulonis said. "Statistically significant improvements in progression-free survival, time to first subsequent therapy, and time to second subsequent therapy, in favor of olaparib, were observed in the overall patient population and in both BRCA-mutant and wild-type subgroups."

"The benefits of olaparib therapy were greatest in the BRCA-mutant subgroup," she added.

Results of the exploratory analysis add to the previously reported primary results, which showed a 65% reduction in the hazard for progression in patients who were randomized to olaparib maintenance after responding to first-line platinum-based chemotherapy.

PARP inhibitors prevent DNA repair in tumor cells that have deficiencies, which occur in as many as 50% of serous ovarian cancers, Matulonis said. BRCA1/2 mutations represent one of the best-known examples of homologous recombination deficiency.

Preliminary clinical trials suggested olaparib has activity in both BRCA-mutant and wild-type high-grade serous ovarian cancers.

Data from the of olaparib maintenance therapy provided an opportunity to evaluate olaparib's clinical impact beyond initial therapy and to continue examination of the effects of BRCA status on the drug's activity.

Using archived samples from the phase II trial, Matulonis and colleagues retrospectively determined BRCA status in 254 of 265 (95.8%) patients. The test results showed that 136 (51.3%) of the patients had BRCA1/2 mutations, and 118 (44.5%) had wild-type tumors. The remaining 11 (4.2%) patients lacked information on BRCA status.

The analysis showed that the PFS benefit of olaparib was most pronounced in the BRCA1/2-mutant subset: 11.2 months versus 4.3 months for placebo-treated patients. The difference translated into an 82% reduction in the hazard for progression (P<0.00001). A 3-month difference in median overall survival (34.9 versus 31.9 months) in favor of olaparib did not achieve statistical significance.

For further analysis, investigators examined the exploratory endpoints TFST (time from randomization to first subsequent therapy or death) and TSST (randomization to second subsequent therapy or death). They had hoped to compare treatment groups with respect to time from randomization to second objective progression or death (PFS), but lacked sufficient data for such an analysis.

Analysis of both endpoints yielded significant advantages for olaparib-treated patients:

• TFST (BRCA+) -- 15.6 versus 6.2 months, P<0.00001
• TFST (wild type) -- 12.9 versus 6.9 months, P=0.00009
• TSST (BRCA+) -- 23.8 versus 15.2 months, P=0.00013
• TSST (wild type) -- 17.1 versus 14.7, P=0.033

The combined analysis (BRCA-mutant and wild type) showed a 60% reduction in the hazard for TFST (HR 0.40, P<0.00001) and a 47% reduction in the hazard for TSST (HR 0.53, P=0.00001).

Invited discussant Elizabeth Swisher, MD, of the University of Washington in Seattle, said the extended clinical benefits observed with olaparib suggest that maintenance therapy with PARP inhibitors does not increase platinum resistance at next relapse, a previously unaddressed issue. The results also showed that BRCA-mutant tumors benefit most from PARP inhibitors. Whether other subgroups benefit more or less remains to be determined.

The favorable results leave multiple unanswered questions about use of PARP inhibitors in the treatment of ovarian cancer, Swisher continued. Whether the agents should be used alone or in combination with chemotherapy or other targeted agents is one of the unknowns. Whether to initiate PARP inhibition as maintenance therapy or at relapse is an open question, as is the optimal timing of initiation of maintenance therapy.

The lack of overall survival benefit could pose problems with peer review organizations, which tend to take a dim view of agents that do not improve survival. Distinguishing features (including toxicity) of different PARP inhibitors have yet to emerge. Most importantly, no one can say with certainty when the PARP inhibitor class will become available for use in clinical practice, said Swisher.

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