A large international phase III randomized controlled trial has found that adding the novel gene therapy ofranergene obadenovec (ofra-vec) to weekly paclitaxel did not improve outcomes in patients with platinum-resistant ovarian cancer. The OVAL study, published on October 31, 2023 in the Journal of Clinical Oncology, was conducted at 86 sites across the United States, Israel, Spain, Poland, and Japan.
The study was funded by VBL Therapeutics, the company developing ofra-vec. It enrolled 409 patients with recurrent platinum-resistant or platinum-refractory epithelial ovarian, primary peritoneal, or fallopian tube cancers between December 2017 and March 2022.
Ofra-vec is a gene-based targeted therapy with a dual mechanism of action - vascular disruption and induction of immune infiltration in solid tumors. It consists of a non-replicating adenoviral vector, a proprietary modified promoter, and a functional proapoptotic transgene. The therapy is designed to selectively target tumor vasculature while sparing normal blood vessels.
The purpose of the OVAL study was to evaluate whether adding ofra-vec to standard weekly paclitaxel could improve progression-free survival (PFS) and overall survival (OS) compared to paclitaxel alone in this difficult-to-treat patient population. Platinum-resistant ovarian cancer has a poor prognosis, with limited effective treatment options available.
Eligible patients had histologically confirmed platinum-resistant or platinum-refractory epithelial ovarian, primary peritoneal, or fallopian tube cancer that progressed within 180 days of last platinum-based therapy. They were required to have measurable disease by RECIST 1.1 criteria. Up to five previous lines of anticancer therapy were allowed, but only two previous lines for platinum-resistant disease. Patients with primary refractory disease, clear cell carcinomas, low-grade tumors, brain metastases, or significant vascular disease were excluded.
The study randomly assigned 409 patients in a 1:1 ratio to receive either intravenous ofra-vec every 8 weeks plus weekly paclitaxel (80 mg/m2) or placebo plus weekly paclitaxel. Randomization was stratified by number of previous treatment lines, previous antiangiogenic therapy, and platinum-free interval.
The demographic and baseline characteristics were well-balanced between the two arms. The median age was around 62 years, and over 90% of patients had high-grade serous ovarian cancer. Patients were heavily pretreated, with a mean of 3 previous lines of therapy. About 63% had received 3 or more previous lines. The majority had previously received PARP inhibitors (63-66%) and anti-angiogenic therapy (69-70%).
The dual primary endpoints were progression-free survival and overall survival, both assessed by blinded independent central review. Secondary endpoints included objective response rate by RECIST and CA-125 criteria.
After a median follow-up of about 13 months, the study found no significant difference in outcomes between the two arms. The median PFS was 5.29 months with ofra-vec plus paclitaxel versus 5.36 months with placebo plus paclitaxel (hazard ratio 1.03, 95% CI 0.83-1.29, p=0.7823). The median OS was 13.37 months versus 13.14 months, respectively (HR 0.97, 95% CI 0.75-1.27, p=0.8440).
Objective response rates were also similar between arms - 28.9% with ofra-vec versus 29.6% with placebo by RECIST criteria. The CA-125 response rates were 41.1% versus 49.4%, respectively.
Interestingly, in both arms, patients who had a CA-125 response showed substantially improved PFS and OS compared to non-responders, confirming the prognostic value of CA-125 response in this setting. For example, in the ofra-vec arm, CA-125 responders had a median PFS of 7.92 months versus 2.79 months for non-responders (HR 0.24).
The safety profile of ofra-vec was generally manageable. The most common adverse events related to ofra-vec were fever (61.1% vs 13.3% with placebo) and chills (27.1% vs 4.9%). These were typically low-grade and resolved within 1-2 days. Rates of adverse events commonly associated with paclitaxel, such as fatigue, anemia, and neuropathy, were similar between arms.
Serious adverse events occurred in 31% of patients receiving ofra-vec versus 26.6% receiving placebo. Treatment discontinuation due to adverse events was low in both arms (3.9% vs 6.9%). There were no new safety signals identified.
The study authors concluded that the addition of ofra-vec to paclitaxel did not improve PFS or OS in patients with platinum-resistant ovarian cancer. They noted that the PFS and objective response rate in the control arm exceeded what was anticipated based on historical data from trials like AURELIA.
There are several limitations to consider when interpreting these results. First, as an adenovirus-based therapy that commonly causes fever, it was difficult to fully blind patients and investigators to treatment assignment. However, there was no evidence of imbalanced withdrawal of consent between arms. Second, the relatively infrequent imaging assessments (every 12 weeks) may have led to overestimation of PFS in both arms compared to trials with more frequent assessments.
Additionally, this was a heavily pretreated population, with most patients having received prior PARP inhibitors and anti-angiogenic therapy. The efficacy of ofra-vec may potentially differ in less heavily pretreated patients. Finally, no predictive biomarkers were identified that could select patients most likely to benefit from ofra-vec.
The negative results of this large phase III trial were disappointing and somewhat unexpected, given the promising phase I/II data and positive interim analysis of CA-125 response rates. This highlights the challenges of drug development in ovarian cancer and the limitations of using surrogate endpoints like CA-125 response to make go/no-go decisions for large phase III trials.
From a clinical perspective, these results do not support the use of ofra-vec in combination with paclitaxel for platinum-resistant ovarian cancer. Weekly paclitaxel remains a reasonable standard option in this setting. The unexpectedly high response rates and PFS observed with weekly paclitaxel alone (exceeding historical benchmarks) suggest this regimen may be more active than previously appreciated in contemporary patient populations.
The strong association between CA-125 response and improved outcomes in both arms reinforces the prognostic value of CA-125 monitoring in platinum-resistant disease. However, the discordance between the interim CA-125 analysis and final PFS/OS results cautions against over-reliance on CA-125 as a surrogate endpoint in clinical trials.
For drug developers, these results emphasize the continued need for randomized phase II studies to derisk large phase III investments, even when early-phase data appear promising. They also highlight the challenges of developing antiangiogenic and vascular-disrupting agents in ovarian cancer, particularly in heavily pretreated populations.
Looking ahead, there remains an urgent need for novel therapies that can meaningfully improve outcomes in platinum-resistant ovarian cancer. Ongoing research is focused on immunotherapy combinations, antibody-drug conjugates targeting novel antigens, and strategies to reverse platinum resistance. Careful patient selection and identification of predictive biomarkers will likely be critical to successfully developing new agents in this challenging disease setting.
In conclusion, while the OVAL trial did not meet its primary endpoints, it provides important data on contemporary outcomes with weekly paclitaxel in platinum-resistant ovarian cancer and reinforces the prognostic value of CA-125 response. As the ovarian cancer treatment landscape continues to evolve, these benchmark data will be valuable for designing future clinical trials in this patient population with high unmet need.
References
Arend RC, Monk BJ, Shapira-Frommer R, et al. Ofranergene Obadenovec (Ofra-Vec, VB-111) With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer: Randomized Controlled Phase III Trial (OVAL Study/GOG 3018). J Clin Oncol. 2024;42(2):170-179. doi:10.1200/JCO.22.02915
