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SAN DIEGO -- Rucaparib (Rubraca) maintenance after first- or second-line chemotherapy improved progression-free survival (PFS) in patients with metastatic or recurrent endometrial cancer, a small phase II randomized trial showed.

Compared with placebo, use of the PARP inhibitor improved PFS by a median 19.4 months (28.1 vs 8.7 months; HR 0.45, 95% CI 0.26-0.80, P=0.005), reported Bradley R. Corr, MD, of the University of Colorado in Aurora.

"Despite ending early, we met our primary endpoint and demonstrated that the use of rucaparib after first- or second-line chemotherapy improves progression-free survival for patients with metastatic and recurrent endometrial cancer in a statistically significant and clinically meaningful manner," Corr said during a plenary presentation at the Society of Gynecologic Oncology (SGO) annual meeting.

The was initially powered to detect a 4-month median PFS improvement, from 8 to 12 months, with 123 patients and an expected number of events of 114 at 23-month follow-up. However, according to Corr, the trial ended early "due to reasons beyond our control," and ended up enrolling 79 patients, with 50 actual events and a median follow-up of 25 months.

Patients in this study were required to have had one or two prior lines of cytotoxic therapy, and no residual disease or a partial or complete response after the most recent regimen.

Subgroup analyses showed a trend toward improved PFS among patients with stage III/IV disease with rucaparib (median 21.1 vs 9.2 months with placebo; HR 0.52, 95% CI 0.27-1.01, P=0.049) and those with recurrent disease (28.5 vs 7.6 months; HR 0.33, 95% CI 0.11-1.03, P=0.046).

Furthermore, patients who had residual disease achieved a greater improvement in PFS (12.8 months with rucaparib vs 5.2 months with placebo; HR 0.23, 95% CI 0.10-0.54, P<0.0001) compared with patients with no residual disease (not reached vs 16.7 months; HR 0.49, 95% CI 0.22-1.13, P=0.09).

As for molecular subgroup analyses, Corr noted "some important trends are present," with the caveat that patient numbers were low.

For example, "it is known that p53-mutant tumors have worse outcomes than wild-type tumors," Corr said. "As expected, the p53-mutant group progressed quicker with placebo than the wild-type group (5.4 months vs 11.7 months). But the use of rucaparib improved the PFS to 11 months in the mutant group."

Since the study met its primary endpoint, Corr also reported overall survival (OS) results. Median OS was not reached in the rucaparib arm and was 28.4 months in the placebo arm (HR 0.48, 95% CI 0.23-1.03, P=0.055).

The primary promise of maintenance "is preventing a recurrence event," said SGO discussant Robert L. Coleman, MD, of Texas Oncology-The Woodlands, noting this was achieved in this study. "So we are hitting this potential benchmark. But ultimately, we'd like to show -- like we saw in Dr. Corr's presentation -- that we're actually affecting overall survival."

However, he added, "context matters."

"It is so important to understand all of the nuances that could potentially confound these results -- stage, primary versus recurrent [disease], molecular characterization," Coleman said. "And what are the most appropriate relevant endpoints?"

How do all of these factors "relate to each other?" he asked, suggesting that in this study -- particularly since it ended before it was fully enrolled -- the sample size was too small to sort out these potentially confounding factors.

Corr noted that the study's "significant positive results raise the obvious question of the comparison with the similar UTOLA trial," a randomized phase IIb trial evaluating olaparib (Lynparza) maintenance after platinum chemotherapy in patients with advanced/metastatic endometrial cancer.

Presented at last year's European Society for Medical Oncology congress, the therapy compared with placebo in the intent-to-treat population of 147 patients, with a median PFS of 5.6 months and 4.0 months, respectively, in the two arms (P=0.36).

"While many variations occur across trials ... there were many key differences," Corr observed. "Despite being the same drug class, there were differences in terms of metabolism and PARP trapping. Furthermore, this trial did not allow stable disease after prior therapy and our trial had a higher rate of patients with no evidence of disease after chemo. This is further evidence that rucaparib is a beneficial maintenance therapy strategy."

The current trial included 39 patients randomized to rucaparib 600 mg twice daily on a 28-day cycle (median age 66, 84.6% white), and 40 patients randomized to placebo on the same schedule (median age 67, 85% white).

Most patients in the rucaparib group had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 (66.7%), 25.6% had stage III disease, 46.2% had stage IV disease, and 28.2% had recurrent disease. For the patients in the placebo group, 70% had an ECOG performance status score of 0, 32.5% had stage III disease, 42.5% had stage IV disease, and 25% had recurrent disease.

Across both groups, most patients had endometrioid histology (51.3-52.5%) or serous histology (27.5-33.3%).

Treatment-related adverse events (TRAEs) were consistent with those reported previously with rucaparib for other tumors, Corr said. The most frequent TRAEs were nausea, fatigue, anemia, thrombocytopenia, and elevated aspartate transaminase/alanine transaminase.

All-grade TRAEs were reported in 95% of patients in the rucaparib arm, and grade ≥3 TRAEs were reported in 36%.

Dose interruptions, reductions, and discontinuations due to TRAEs occurred in 36%, 33%, and 8% of patients in the rucaparib arm, respectively.

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