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Patients with ovarian cancer that progressed following maintenance therapy with olaparib (Lynparza) had a significantly shorter time to second progression when treated with platinum-based chemotherapy, a new analysis of a randomized trial showed.

The median time to second progression (TTSP) with any chemotherapy was 6.9 months for patients initially randomized to the PARP inhibitor (PARPi) versus 12.1 months for patients allocated to placebo. Patients who received platinum-based chemotherapy accounted for most of the difference -- 7.0 months for the olaparib group versus 14.3 months for placebo-treated patients. TTSP was similar for the olaparib and placebo groups when treated with non-platinum chemotherapy.

The hypothesis-generating findings are provocative and require further investigation to sort out the explanations for the difference in TTSP, reported Jean-Sebastien Frenel, MD, of Institut de Cancerologie de l'Ouest in Saint-Herblain, France, and co-authors in the .

The exploratory analysis "suggests that PARPi maintenance therapy may reduce the efficacy of subsequent platinum-based chemotherapy," the authors wrote in their discussion of the findings. "This difference remained significant in multivariable analysis and also in the sensitivity analyses excluding patients who received maintenance PARPi following platinum-based chemotherapy."

"Maintenance PARPi have significantly improved outcome for PSROC [platinum-sensitive relapsed ovarian cancer]," they added. "In patients with BRCA1/2 mutation, olaparib is associated with significant prolongation of PFS [progression-free survival] and also numerical improvement in OS [overall survival]. ... Despite the potential for diminished efficacy of subsequent platinum chemotherapy following progression on olaparib, PARPi should still be offered to all eligible patients as maintenance therapy."

Similar findings have come from other retrospective assessments of maintenance PARPi's effect on response to post-PARPi platinum-based chemotherapy, noted the authors of an .

"These observations are significant, as acquired resistance to PARPi overlaps with platinum resistance," wrote Rebecca S. Kristeleit, MD, of Guy's and St. Thomas' NHS Foundation Trust in London, and Kathleen Moore, MD, of the University of Oklahoma Health Sciences Center in Oklahoma City. "Concern about short-term gains in PFS being compromised by downstream impact on response to subsequent therapies is valid."

The analysis had a number of limitations, beginning with the retrospective nature of the work, Kristeleit and Moore continued. Additionally, the study included only patients with confirmed RECIST progression, which resulted in an imbalance between the two arms (more in the olaparib arm). Beyond that, not all patients received chemotherapy at progression.

The analysis covered a relatively short follow-up period of 15 to 17 months. The prevalence of BRCA reversion mutations, which are predictors of response to PARPi and platinum chemotherapy, was unknown.

"Due to these limitations, a highly selected, imbalanced, poorer prognosis subset of the olaparib-treated population has been analyzed that may not be represented of the whole population with respect to subsequent platinum response," noted Kristeleit and Moore. "But, is it plausible that PARPi use in the PSROC maintenance setting until RECIST PD [progression] and PARPi resistance, is negatively impacting benefit from platinum-based chemotherapy?"

"As multiple cross-resistant pathways to PARPi and platinum exist (and co-exist), the findings in this study are plausible," they concluded.

Frenel and co-authors reported findings from a post-hoc subgroup analysis of the international randomized phase III SOLO2/ENGOT Ov21 trial that established maintenance therapy with olaparib as a standard of care for patients with platinum-sensitive relapsed ovarian cancer. The analysis included 147 patients who received chemotherapy as their first subsequent therapy after progression on olaparib or placebo. The total comprised 69 placebo-treated patients and 78 randomized to olaparib.

Subsequently, 27 placebo patients received non-platinum chemotherapy and the remaining 42 received platinum chemotherapy. Among patients originally randomized to olaparib maintenance, 24 received non-platinum chemotherapy and 54 received platinum chemotherapy. The primary endpoint was TTSP, calculated from the time of initial RECIST progression to subsequent progression or death.

The analysis of all 147 patients showed that olaparib maintenance therapy was associated with more than a twofold increase in the TTSP hazard (HR 2.17, 95% CI 1.47-3.19). The analysis limited to patients who received platinum chemotherapy showed almost a threefold increase in the hazard among patients originally randomized to olaparib maintenance therapy (HR 2.89, 95% CI 1.72-4.82).

In contrast, patients who received non-platinum chemotherapy had a median TTSP of 8.3 months versus 6.0 months for those treated with a platinum agent, a difference that did not achieve statistical significance (HR 1.58, 95% CI 0.86-2.90).

The authors acknowledged that the TTSP endpoint used in the analysis has not been widely used in trials of PARPi therapy for ovarian cancer. More common endpoints include time to first subsequent treatment, time to second subsequent treatment, and second progression-free survival (PFS2).

"In contrast to PFS2, TTSP provides a different insight into the efficacy of subsequent therapies, given that it does not include the impact of the initial PARPi maintenance therapy," they wrote. "However, our analysis only evaluated those patients who had progressed on randomized therapies and excluded those who showed no disease progression. Nevertheless, the decreased TTSP observed in this study for platinum-based treated patients who had earlier progressed under olaparib did not represent a reversal of the benefits of olaparib maintenance."

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