PARP Inhibition Shines at ESMO Amid Negative Ovarian Trials

By Chase Doyle

PARP inhibition continues to steal the spotlight in advanced ovarian cancer, even in the absence of pivotal trial data.

Findings presented at the European Society of Medical Oncology (ESMO) Virtual Congress 2020 showed a significant benefit for PARP inhibition earlier in the cancer pathway, offering hope for more long-term survivors, while other treatment paradigms such as immunotherapy failed again to make headway against the disease.

The following are highlights from advanced ovarian cancer trials presented at the meeting.

Earlier Olaparib Therapy Provides Better Chance of Long-Term Remission

When it comes to PARP inhibition, the earlier, the better, according to the longest follow-up analysis for any PARP inhibitor in the first-line maintenance setting.1

Results of the phase III SOLO1 trial, presented by Susana Banerjee, MBBS, PhD, of The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, in London, showed that nearly half of patients who received the PARP inhibitor olaparib for newly diagnosed, BRCA-mutated advanced ovarian cancer remained disease-free after five years.

“These results represent a significant step forward in the treatment of newly diagnosed advanced ovarian cancer and give us real hope for more long-term survivors,” said Dr. Banerjee, who noted that previous research in PARP inhibitors in ovarian cancer has only been in patients with relapsed disease.

As Dr. Banerjee reported, patients with newly diagnosed advanced ovarian cancer are at high risk of relapse, and 5-year survival is only 30% to 50%. SOLO1 randomized patients with BRCA-mutated ovarian cancer (n=260) to maintenance olaparib versus placebo following first-line response to platinum-based chemotherapy. Patients were treated for up to two years or until disease progression.

Five-year follow-up data from the study showed that 48.3% of patients treated with olaparib had not experienced disease progression and were still living with stable disease compared with only 20.5% of patients who received placebo. The median progress-free survival (PFS) was 56 months on olaparib versus 13.8 months with standard treatment only, and no new safety signals were observed.

Atezolizumab Fails to Improve Outcomes in Newly Diagnosed Advanced Disease

Once again, immunotherapy has failed to make progress in ovarian cancer.

The addition of atezolizumab, an anti-PD-L1 inhibitor, to chemotherapy and bevacizumab showed no benefit in newly diagnosed advanced ovarian cancer versus chemotherapy and bevacizumab alone, according to the results of a large international trial.2

“Despite notable successes with incorporation of atezolizumab and bevacizumab in the treatment of other solid tumors, the trial failed to meet its first primary endpoint for extending PFS in either the intention-to-treat or fully powered PD-L1-positive population,” said Kathleen Moore, MD, of the University of Oklahoma Sciences Center in Oklahoma City.

For the IMagyn050 trial, Dr. Moore and colleagues enrolled 1,301 patients with untreated stage III/IV epithelial ovarian, primary peritoneal, or fallopian tube cancer. Patients had postoperative macroscopic residual disease or planned neoadjuvant chemotherapy with planned interval surgery. All patients received carboplatin, paclitaxel, and bevacizumab and were randomized to placebo or atezolizumab.

As Dr. Moore reported, patients receiving atezolizumab in addition to chemotherapy and bevacizumab had a median PFS of 19.5 months versus 18.4 months without the immunotherapy boost, but this 1-month difference was not statistically significant.

Subgroup analysis showed a 2.3 month improvement in PFS in PD-L1-positive patients (≥1% immune cell expression) randomized to atezolizumab, but this also failed to not meet prespecified criteria for statistical difference.

An exploratory analysis of patients with greater than 5% PD-L1 expression, however, showed evidence of improved PFS with atezolizuma.

“The signal of a clinical benefit for atezolizumab in the immune cell PD-L1-high subgroup may warrant further evaluation,” Dr. Moore observed.

The interim analysis of overall survival (OS) showed no differences between treatment groups, but a final analysis will be expected and presented in 2023, Dr. Moore concluded.

Platinum-Based Regimens Remain Standard of Care in Recurrent Platinum-Sensitive Disease

Trabectedin, a chemotherapy drug approved for advanced soft tissue sarcoma, has failed to demonstrate improved survival versus standard of care in patients with recurrent disease progressing 6 to 12 months after their last platinum treatment.3

According to results of the phase III INOVATYON trial, presented by Nicolette Colombo, MD of the European Institute of Oncology IRCCS and University of Milan-Biococca in Italy, median survival was 21.5 months with trabectedin plus pegylated liposomal doxorubicin (PLD) and 21.3 months with carboplatin/PLD. Median PFS also significantly favored the carboplatin versus trabectedin arm (9.0 vs. 7.5 months, respectively).

“The study did not meet its primary endpoint,” said Dr. Colombo. “It failed to demonstrate an improvement in OS for trabectedin/PLD. Platinum-based regimens remain the standard of care in patients with recurrent ovarian cancer progressing within 6 to 12 months after their last platinum line.”

Although trabectedin is not approved for ovarian cancer in the U.S., it has regulatory approval for platinum-sensitive ovarian cancer elsewhere in the world based on results of the OVA-301 and OVA-3006 trials, which showed a survival benefit in BRCA-mutant tumors and in patients with a platinum-free interval of 6 to 12 months.4,5

The INOVATYON trial, initiated in 2011 prior to the results of OVA-301 and OVA-3006, aimed to demonstrate an improvement in OS with trabectedin plus PLD after relapse. Dr. Colombo and colleagues randomized 617 patients from 117 European sites to trabectedin plus PLD every 3 weeks or carboplatin plus PLD every 4 weeks. Platinum rechallenge was mandatory in the trabectedin arm following progression but was at the physician’s discretion in the carboplatin arm.

The phase III INOVATYON trial did not meet its primary endpoint of OS, showing no benefit of trabectedin plus PLD versus carboplatin plus PLD in recurrent ovarian cancer.

After subsequent treatment with a platinum agent, however, trabectedin plus PLD did convey significantly longer PFS (7.4 months with trabectedin/PLD vs 5.7 months with carboplatin/PLD). The trabectedin combination was also favored among patients who had received two prior lines of treatment, Dr. Colombo reported.

Given similar OS outcomes, trabectedin/PLD can still be considered in patients who need longer recovery from platinum-specific toxicities, authors of the study noted.

Dose-Dense Chemotherapy Not Superior to Standard of Care

Weekly dose-dense chemotherapy offers no added benefit for patients with epithelial ovarian cancer versus standard chemotherapy administered every three weeks.6

Presented by Andrew Clamp, MD, of The Christie NHS Foundation Trust, mature survival data from the ICON8 trial provided conclusive evidence that dose-dense chemotherapy with paclitaxel or paclitaxel/carboplatin does not improve OS or PFS versus standard chemotherapy.

“This final analysis confirms results of the previously published PFS analysis,” said Dr. Clamp. “Weekly dose-dense chemotherapy is a well-tolerated alternative to standard chemotherapy for epithelial ovarian cancer, but it provides no PFS or OS advantage.”

For this study, Dr. Clamp and colleagues randomized 1,566 patients with epithelial ovarian cancer (Stage IcG3–IV) to standard chemotherapy (carboplatin every 3 weeks plus paclitaxel every 3 weeks), weekly paclitaxel (carboplatin every 3 weeks plus weekly paclitaxel) or weekly carboplatin/paclitaxel (weekly carboplatin plus weekly paclitaxel).

Prior to enrollment, patients either had either undergone immediate primary surgery or received neoadjuvant chemotherapy with planned delayed primary surgery during chemotherapy. The study’s co-primary outcomes were PFS and OS.

As Dr. Clamp reported, data showed no difference in death rate between standard chemotherapy (61%) and either weekly paclitaxel (57%) or weekly carboplatin/paclitaxel (58%), and the median OS did not differ between study arms.

The updated PFS results support the original analysis, said Dr. Clamp, with no significant difference in PFS observed between study arms. The restricted mean PFS durations in the standard chemotherapy, weekly paclitaxel and weekly carboplatin/paclitaxel arms were 25.0 months, 25.5 months and 25.9 months, respectively.

According to Dr. Clamp, surgical approach had no impact on survival outcomes.

References

  1. Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation: 5-year follow-up from SOLO1. Presented at: ESMO Virtual Congress 2020; September 19-21, 2020. Abstract 811MO.
  2. Moore KN, Bookman M, Sehouli J, et al. Primary results from IMagyn050/GOG 3015/ENGOT-OV39, a double-blind placebo-controlled randomized phase III trial for newly diagnosed stage III/IV ovarian cancer. Presented at: ESMO Virtual Congress 2020; September 19-21, 2020. Abstract LBA31.
  3. Colombo N, Gadducci A, Sehouli J, et al. INOVATYON study: randomized phase III international study comparing trabectedin/PLD followed by platinum at progression vs carboplatin/PLD with recurrent ovarian cancer progressing within 6-12 months after last platinum line. Presented at: ESMO Virtual Congress 2020; September 19-21, 2020. Abstract LBA30.
  4. Poveda A, Vergote I, Tjulandin S, et al. Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol. 2011 Jan;22(1):39-48.
  5. Kaye SB, Colombo N, Monk BJ, et al. Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval. Ann Oncol. 2011 Jan;22(1):49-58.
  6. Clamp AR, James EC, McNeish I, et al. ICON8: Overall survival results in a GCIG phase III randomised controlled trial of weekly dose-dense chemotherapy in first line epithelial ovarian, fallopian tube or primary peritoneal carcinoma treatment. Presented at: ESMO Virtual Congress 2020; September 19-21, 2020. Abstract 805O.