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'Potential Detrimental Effect' With Fourth-Line Olaparib in Ovarian Cancer

— Post-hoc data from SOLO3 show diverging results based on prior lines of therapy

Ƶ MedicalToday

NEW YORK -- A post-hoc analysis of overall survival (OS) in the SOLO3 trial demonstrated why olaparib (Lynparza) recently had its fourth-line indication in ovarian cancer by drugmaker AstraZeneca.

The phase III trial, which tested olaparib versus non-platinum chemotherapy for women with BRCA-mutated platinum-sensitive relapsed disease, found diverging OS signals based on whether women had received two or three prior lines of therapy, Charles Leath III, MD, MSPH, of the University of Alabama at Birmingham, reported here.

In women who received two prior lines of chemotherapy, the median OS was 37.9 months with olaparib, as compared with 28.8 months for those who received chemotherapy (HR 0.83, 95% CI 0.51-1.38).

On the other hand, for patients who previously received three or more lines of prior therapy, a "potential detrimental effect" was seen, with a median OS of 29.9 months versus 39.4 months, respectively (HR 1.33, 95% CI 0.84-2.18), Leath noted.

"Patients with two prior lines of chemotherapy had a numerically favorable overall survival and progression-free survival [PFS] with olaparib over chemotherapy," Leath said in a presentation at the International Gynecologic Cancer Society annual meeting.

PFS was 16.4 months with olaparib compared with 9.0 months with chemotherapy in women with two prior lines (HR 0.46, 95% CI 0.29-0.75), but no different for those who received three or more lines (9.4 vs 9.2 months, respectively; HR 0.87, 95% CI 0.55-1.45).

Olaparib, a PARP inhibitor, had received accelerated approval from the FDA in 2014 for the treatment of advanced BRCA-mutated ovarian cancer based on results demonstrating an improved objective response rate (ORR) and duration of response in a single-arm phase II study of patients who received three or more lines of chemotherapy. Following this approval, however, the agency requested a confirmatory trial.

confirmed a statistically significant improvement in ORR and PFS with olaparib over single-agent non-platinum chemotherapy (paclitaxel, topotecan, gemcitabine, or pegylated liposomal doxorubicin) in patients who had received two or more lines of chemotherapy.

A lack of OS benefit in other confirmatory trials like SOLO3 have haunted the PARP inhibitor class of late. Recently, the American Society of Clinical Oncology (ASCO) warned against routine use of PARP inhibitor monotherapy in the second- or later-line setting for patients with recurrent platinum-sensitive ovarian cancer, following the emergence of "practice-changing" data from three phase III clinical trials, including the OS analysis of SOLO3.

In the most recent post-hoc analysis, Leath and colleagues assessed OS and PFS in women who received two lines of chemotherapy compared with three or more lines. Of these patients, 178 received olaparib, and 88 received chemotherapy. The proportion of patients who received two versus three or more previous lines of chemotherapy was similar in both treatment arms. Most patients in both arms had a BRCA1 mutation.

Leath and colleagues did not observe any new safety signals in the post-hoc analysis. Adverse events were consistent with the known safety profile of olaparib and previous SOLO3 analyses.

In total, 22% of patients who received olaparib developed secondary BRCA reversion mutations at disease progression, a mechanism of resistance to PARP inhibitors and platinum-based chemotherapy, Leath explained. He said that further research will explore whether BRCA reversions in patients who received olaparib will change clinical outcomes.

Leath noted that this post-hoc subgroup analysis was not powered for formal significance testing.

  • Amanda D'Ambrosio is a reporter on Ƶ’s enterprise & investigative team. She covers obstetrics-gynecology and other clinical news, and writes features about the U.S. healthcare system.

Disclosures

This study was funded by AstraZeneca.

Leath disclosed relevant financial relationships with Merck, Seattle Genetics, Immunogen, and Natera.

Primary Source

International Gynecologic Cancer Society

Leath C, et al "Overall survival by number of prior lines of chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer receiving olaparib treatment or non-platinum chemotherapy in SOLO3" IGCS 2022; Abstract LB001.