Richard T. Penson, MD, MRCP

Sarah M. Temkin, MD

Compared with treatment with nonplatinum-based chemotherapy, monotherapy with the PARP (poly [ADP ribose] polymerase) inhibitor olaparib led to statistically significant and clinically relevant improvements in overall response rate and progression-free survival in women with germline BRCA-mutated, platinum-sensitive relapsed ovarian cancer, according to the phase III SOLO3 trial. These data were originally presented at the 2019 ASCO Annual Meeting by Richard T. Penson, MD, MRCP, Clinical Director of Medical Gynecologic Oncology at Massachusetts General Hospital in Boston, and colleagues. The study was later discussed at the Best of ASCO Austin by Sarah M. Temkin, MD, Director of Gynecologic Oncology at Anne Arundel Medical Center, Annapolis, Maryland, along with other top selected abstracts in gynecologic cancer.^1,2

‘Big News’ in Recurrent Ovarian Cancer

According to Dr. Temkin, incorporating maintenance PARP inhibitors into the primary treatment of ovarian cancer was the “big news of 2019” in regard to new gynecologic cancer research at the ASCO meeting. However, she said, there remain many questions as to how to safely and effectively use PARP inhibitors to treat women with ovarian cancer.

“Not only in patients who carry a BRCA mutation but in those who do not, we still don’t know when to start and stop therapy,” stated Dr. Temkin. “And for patients with ovarian cancer who have traditionally relished their chemotherapy breaks—which we’ve always thought were safe and encouraged—will they now not receive any chemotherapy holidays?”

Dr. Temkin added that the consequences of treating—or not treating—women with PARP inhibitors are still unclear. “There’s some anxiety that using PARP inhibitors early may limit the ability of patients to tolerate subsequent therapies,” she observed.

However, according to data from the phase III SOLO3 trial, treatment with the PARP inhibitor olaparib may be a reasonable alternative to chemotherapy for women with a BRCA mutation and platinum-sensitive recurrent ovarian cancer.

Higher Response Rates With Olaparib

In the SOLO3 trial, platinum-sensitive patients with relapsed high-grade serous or endometrioid ovarian, primary peritoneal, and/or fallopian tube cancer, and a germline BRCA mutation who has undergone two or more previous lines of platinum-based chemotherapy, were randomly assigned 2:1 to receive olaparib at 300 mg twice daily (n = 178) or nonplatinum-based chemotherapy of physician’s choice (n = 88). The primary endpoint was overall response rate, assessed by blinded independent central review. Secondary endpoints included progression-free survival and safety.

‘Chemotherapy-free’ treatment is a reasonable option for women with a BRCA mutation and platinum-sensitive recurrent ovarian cancer.

— Sarah M. Temkin, MD

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“The important thing to note about this trial is that these patients were all platinum-sensitive,” Dr. Temkin said. “The standard-of-care arm was nonplatinum single-agent chemotherapy. Most people would agree that a carboplatin doublet is usually recommended in this setting, but with more than two lines of carboplatin, you start running into patients’ tolerance of doublet therapy and also carboplatin allergies.”

Patients were well matched in terms of disease site and presence of BRCA1 or BRCA2 mutations. The majority of patients experienced disease progression between 6 and 12 months after their last platinum therapy, and the vast majority had received two lines of prior therapy. Patients generally had a very good performance status, and in the chemotherapy arm, most patients received pegylated liposomal doxorubicin as standard-of-care therapy. Other chemotherapies included paclitaxel, gemcitabine, and topotecan.

According to Dr. Temkin, the overall response rates were “quite remarkable.” Patients who received olaparib had higher response rates and were more likely to respond. In all patients, the overall response rate was 72% with olaparib, compared with 51% with chemotherapy, with an odds ratio of response of 2.53 (P = .002).

Responses were also more pronounced in patients who received the PARP inhibitor with less prior therapy. The overall response rate in patients with two prior lines of chemotherapy was 85% with olaparib vs 62% with chemotherapy, compared with 59% and 39% for olaparib and chemotherapy, respectively, in those with three or more prior lines of chemotherapy.

Blinded independent central review results for progression-free survival were similar to investigator-assessed results, demonstrating that a single-agent PARP inhibitor in this setting improved progression-free survival from 9 to 13.5 months in both groups. “We would all agree that that’s a clinically significant improvement in progression-free survival,” Dr. Temkin noted.

The tolerability profiles of the study treatments were as expected. Patients who received olaparib experienced more anemia, thrombocytopenia, and other hematologic toxicities, whereas patients who received chemotherapy had more neutropenia and palmar-plantar erythrodysesthesia. Patients treated with chemotherapy were also more likely to discontinue study treatment due to an adverse event (20% vs 7%).

“The investigators’ conclusion—and I would agree with it—is that ‘chemotherapy-free’ treatment is a reasonable option for women with a BRCA mutation and platinum-sensitive recurrent ovarian cancer,” Dr. Temkin reported. ■

DISCLOSURE: Dr. Temkin has served as a consultant or advisor to Incyte and has received institutional research funding from Aprea Therapeutics and MacroGenics. Disclosure information for Dr. Penson and colleagues can be found at coi.asco.org.

REFERENCES

1. Penson RT, Valencia RV, Cibula D, et al: Olaparib monotherapy versus chemotherapy for germline BRCA-mutated platinum- sensitive relapsed ovarian cancer patients: Phase III SOLO3 trial. 2019 ASCO Annual Meeting. Abstract 5506. Presented June 3, 2019.

2. Temkin SM: Gynecologic cancer. 2019 Best of ASCO Austin. General Session. Presented July 27, 2019.