Olaparib improves response, PFS over chemo in relapsed, BRCA mutated, platinum-sensitive ovarian cancer
Women with platinum-sensitive ovarian cancer with germline BRCA mutations who relapsed after previously receiving ≥2 lines of chemotherapy demonstrated better objective response rates (ORRs) and progression-free survival (PFS) following treatment with olaparib than platinum-based chemotherapy, according to results of the SOLO3* trial.
The multinational phase III trial involved 266 women with platinum-sensitive relapsed, high-grade serous or endometrioid ovarian, primary peritoneal, and/or fallopian tube cancer and germline BRCA mutations who had previously received ≥2 lines of platinum-based chemotherapy. They were randomized 2:1 to receive either oral olaparib (300 mg BID; n=178) or non-platinum chemotherapy (PLD, paclitaxel, gemcitabine, or topotecan; n=88).
ORR was superior among olaparib compared with chemotherapy recipients (odds ratio [OR], 2.53, 95 percent confidence interval [CI], 1.40–4.58; p=0.002). [ASCO 2019, abstract 5506]
Among the 151 olaparib recipients, ORR was 72 percent, with 63 and 9 percent having partial and complete responses, respectively. Of the 72 chemotherapy recipients, ORR was 51 percent, with 49 and 3 percent having partial and complete responses, respectively.
This improved ORR appeared particularly evident among women who had received two prior lines of chemotherapy (ORR, 85 percent [olaparib] vs 62 percent [chemotherapy], OR, 3.44, 95 percent CI, 1.42–8.54) compared with those who had received ≥3 prior lines of chemotherapy (ORR, 59 percent vs 39 percent, OR, 2.21, 95 percent CI, 0.96–5.20).
“The biggest message is to take the PARP** inhibitors up front and we hope to cure people. The earlier the treatment, the better,” study author Dr Richard Penson from the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, US, told The ASCO Post.
PFS was also longer among those assigned to olaparib vs chemotherapy, both in the blinded investigator central review (median, 13.4 vs 9.2 months, hazard ratio [HR], 0.62, 95 percent CI, 0.43–0.91; p=0.013) and investigator-assessed analyses (median, 13.2 vs 8.5 months, HR, 0.49, 95 percent CI, 0.35–0.70; p<0.001). Time to first subsequent therapy, according to investigator analyses, was also longer in the olaparib vs chemotherapy arm (median, 15.1 vs 10.2 months, HR, 0.48; p<0.001).
At present, data on overall survival is immature. There was little difference in terms of health-related quality of life between olaparib and chemotherapy recipients.
Serious adverse event (AE) incidence was higher among olaparib vs chemotherapy recipients (24 percent vs 18 percent). AE-related dose interruptions occurred in 48 and 42 percent of olaparib and chemotherapy recipients, respectively, and dose reductions in 27 and 33 percent, respectively. Chemotherapy recipients were almost three times more likely to discontinue treatment due to AEs than olaparib recipients (20 percent vs 7 percent). The most common grade ≥3 AEs among olaparib recipients were anaemia (21.3 percent) and neutropenia (9.6 percent), and among chemotherapy recipients, neutropenia (15.8 percent) and palmar-plantar erythrodysesthesia (11.8 percent).
Three patients in the olaparib arm developed new malignancies (one each of lung, breast, and gastric cancer), while acute myeloid leukaemia and myelodysplastic syndromes occurred in four and three patients in the olaparib and chemotherapy arms, respectively.
“We know that ovarian cancer that’s associated with a mutation in BRCA does respond quite favourably to the PARP inhibitors … these agents are approved in multiple settings in ovarian cancer specifically in patients undergoing treatment in the first line,” said discussant Dr Don Dizon from the Lifespan Cancer Institute, Rhode Island, US, to The ASCO Post.
The question now is whether chemotherapy is necessary to treat recurrence “and the answer is probably not”, said Dizon.
Penson pointed out that while the SOLO3 findings demonstrate a “therapeutic advantage [of olaparib] over palliative single agent chemotherapy, it does not address the question of what is wrong with platinum in the third-line [setting]”.