ONA-XR/Anastrozole Combo Delivers Promising Early Results in HR+ Metastatic Endometrial Cancer

Oral progesterone receptor antagonist onapristone extended release (ONA-XR) in combination with anastrozole induced a confirmed partial response in 2 patients with hormone receptor (HR)–positive metastatic endometrial cancer, according to early results from the ongoing phase 2 OATH trial (NCT04719273).¹

As of the September 30, 2022, data cutoff, 9 of the first 12 enrolled patients were evaluable for efficacy. Preliminary data showed that ONA-XR plus anastrozole demonstrated a 4-month progression free survival rate of 77% and an overall response rate of 22%.

The company said these results demonstrate that this combination has favorable efficacy and tolerability compared with results from the phase 3 KEYNOTE-775 trial (NCT03517449) evaluating physician’s choice of doxorubicin or paclitaxel vs lenvatinib (Lenvima) plus pembrolizumab (Keytruda) in this patient population.²

In KEYNOTE-775, the 4-month PFS rate was 67% for the lenvatinib/pembrolizumab combination and 42% for chemotherapy. The ORR was 32% and 14%, respectively.

“Data from the ongoing phase 2 OATH clinical trial supports the potential for ONA-XR plus anastrozole combination therapy to serve as an effective therapeutic option in metastatic endometrial cancer,” Martin Lehr, chief executive officer of Context Therapeutics, said in a news release. “We are encouraged by these findings and look forward to continued enrollment in the trial.”

Endometrial cancer is the most common gynecologic cancer in the United States and the fourth leading cause of cancer-related mortality in women.³ The American Cancer Society says there were an estimated 65,950 new diagnoses in 2022 with more than 13,000 deaths.⁴

Current treatments are limited, with platinum plus taxane combination chemotherapy being the standard of care for first-line metastatic disease. After first-line therapy, patients are typically treated with additional toxic infusion therapies, including chemotherapy or lenvatinib plus pembrolizumab combination therapy.

Furthermore, grade 3 or higher adverse effects (AE) including diarrhea, nausea, vomiting, and hypertension are common with current treatment options. Clinician and patient feedback indicates a high unmet need for a novel orally administered therapeutic that provides toxic therapy–like efficacy but with fewer debilitating AEs.

In KEYNOTE-775, 89% of patients assigned to the combination and 73% of patients assigned to chemotherapy experienced grade 3 or higher AEs. In contrast, most AEs in the OATH study were grade 1/2.

ONA-XR, an oral, twice-a-day, selective PR antagonist designed to block both ligand-dependent and ligand-independent activity of PR, has not been approved for marketing by any regulatory authority.

Context is also evaluating ONA-XR in combination with selective estrogen receptor degraders for patients with breast cancer in 2 ongoing trials. The phase 1b/2 ELONA trial (NCT05618613) is evaluating the combination of ONA-XR plus the recently approved elacestrant (Orserdu) for patients with advanced or metastatic estrogen receptor (ER)–positive, progesterone receptor (PR)–positive, HER2-negative breast cancer. Investigators are also evaluating the combination of ONA-XR plus fulvestrant for patients with ER-positive, PR-positive or -negative, and HER2-negative locally advanced or metastatic breast cancer following progression on aromatase and CDK4/6 inhibitors in the phase 2 SMILE trial (NCT04738292).

References

1. Context Therapeutics highlights clinical responses from the phase 2 OATH clinical trial evaluating ONA-XR for the treatment of endometrial cancer. News release. Context Therapeutics. February 6, 2023. Accessed February 8, 2023. https://ir.contexttherapeutics.com/news-releases 
2. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330.
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30. Published online January 8, 2020. doi:10.3322/caac.21590
4. Key statistics for endometrial cancer. American Cancer Society. January 12, 2023. Accessed February 8, 2023. https://www.cancer.org/cancer/endometrial-cancer/about/key-statistics.html