番茄社区

NATIONAL HARBOR, Md. -- Maintenance therapy with a PARP inhibitor led to a big improvement in progression-free survival (PFS) for some patients with ovarian cancer but maintenance chemotherapy did not, according to studies reported here.

Women with relapsed, platinum-sensitive, BRCA-mutated ovarian cancer had a median PFS of 19.1 months with olaparib (Lynparza) maintenance therapy as compared with 5.5 months for placebo-treated patients.

All key secondary endpoints improved significantly with PARP inhibitor maintenance, including time to next therapy, second PFS (PFS2), and time to second subsequent therapy, investigators in a multicenter, international trial reported at the (SGO) meeting.

"SOLO2 is the first phase III trial of olaparib tablets as maintenance treatment and showed a significant benefit in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation," said , of the University of Paris.

The results were impressive but only time will tell whether olaparib wins the day as maintenance therapy in ovarian cancer, said , of Massachusetts General Hospital Cancer Center in Boston. Another PARP inhibitor (rucaparib, Rubraca) received FDA approval late last year, and a recently reported trial of niraparib showed broad activity in patients with advanced ovarian cancer.

"The phase II trial of olaparib showed an overall benefit, irrespective of BRCA status, but the best results occurred in patients with BRCA mutations," said Dizon, who chaired the late-breaking abstract session that included the SOLO2 report. "The niraparib study clearly showed a benefit in an unselected patient population. I think the take-home message for now is that maintenance therapy with a PARP inhibitor is beneficial."

Maintenance chemotherapy did not fare so well in a reported at SGO. Maintenance with conventional paclitaxel or a polymer-conjugated formulation of the drug did not improve overall survival (OS) compared with surveillance, as median survival ranged between 51 and 60 months among three randomized groups.

Olaparib Trial Results

Pujade-Lauraine reported findings from the phase III SOLO2 trial, involving patients with relapsed BRCA-mutated ovarian cancer still in response to the most recent platinum-based chemotherapy. Olaparib received FDA accelerated approval as maintenance therapy on the basis of results of a phase II trial that showed improved PFS in unselected patients but more prolonged progression-free intervals in the subgroup with BRCA-mutated disease.

SOLO2 continued evaluation of olaparib in patients with BRCA-mutated ovarian cancer. Additionally, the trial evaluated a tablet formulation of olaparib that substantially reduced the pill burden from the phase II trial, involved a capsule formulation of olaparib.

Investigators in SOLO2 randomized patients 2:1 to olaparib or placebo, and treatment continued until disease progression. The primary endpoint was investigator-assessed PFS. Data analysis comprised 295 patients.

The trial met the primary endpoint, showing a 70% reduction in the hazard for progression or death in patients treated with olaparib (95% CI 0.22-0.41, P<0.0001).

The median time to first subsequent therapy was 27.9 months with olaparib versus 7.1 months with placebo (HR 0.28, P<0.0001). The median PFS had yet to be reached in the olaparib group compared with a median of 18.4 months with placebo (HR 0.50, P=0.0002). The placebo group had an 18.2-month median time to second subsequent therapy, whereas the median had yet to be reached with olaparib (HR 0.37, P<0.0001).

Analysis of adverse events showed no new or unexpected safety issues with olaparib. Nausea, fatigue, vomiting, diarrhea, dysgeusia, headache, abdominal pain, decreased appetite, constipation, and anemia all occurred in 20% or more of patients treated with olaparib. The most frequent grade ≥3 adverse events with olaparib were anemia (19.5%), fatigue/asthenia (4.1%), vomiting (2.6%), abdominal pain (2.6%), nausea (2.6%), and diarrhea (1.0%)

Maintenance Chemotherapy

The phase III Gynecologic Oncology Group (now part of the NRG intergroup) 212 trial evaluated maintenance therapy with two formulations of paclitaxel. Neither formulation improved survival compared with surveillance in patients with surgically resected, platinum-sensitive ovarian cancer, reported , of Ohio State University in Columbus.

The trial had its genesis in the recognition that many patients with advanced ovarian cancer attain a complete clinical response with surgery and chemotherapy. However, patients in complete response have a high probability of recurrence. Whether maintenance therapy for patients in complete remission would reduce recurrent and improve survival remained unclear.

GOG 212 involved 1,157 patients in complete response after surgery and chemotherapy. They were randomized to conventional surveillance practices or to two groups of paclitaxel maintenance therapy. One group received conventional paclitaxel and the other received CT-2103, a paclitaxel-polyglutamate polymer conjugate that achieves higher tissue concentrations of the drug.

The trial had OS as its primary endpoint. When the trial ended after a median follow-up of 71 months, the paclitaxel and CT-2103 arms had a median OS of 51.3 and 60 months, not significantly different from the 55-month median in the surveillance group.

Analysis of the secondary endpoint of PFS showed a median of 18.9 months with conventional paclitaxel, 16.3 months with CT-2103, and 13.4 months with surveillance. The PFS with paclitaxel proved to be significant versus surveillance (HR 0.783, 95% CI 0.666-0.921), as did the difference in the CT-2103 arm (HR 0.847, 95% CI 0.721-0.995). However, Copeland reiterated the secondary-endpoint status of PFS.

Patients with no residual disease after surgery (R0 status) had better survival (median OS 70.0 versus 43.6 months). An exploratory analysis showed no advantage to the addition of maintenance chemotherapy.

Investigators also explored the question of whether maintenance therapy might actually induce chemoresistance. They found that patients with residual disease did slightly worse with chemotherapy (median OS approx. 40 months versus approx. 49 months with surveillance), though neither difference achieved statistical significance.