The FDA Grants BTD to R-DXd in Pretreated Gynecologic Cancers

Findings from a phase 1 and the REJOICE-Ovarian01 trials supported the FDA’s decision to grant the designation to R-DXd in those with gynecologic cancers.

The FDA has granted breakthrough therapy designation (BTD) to raludotatug deruxtecan (R-DXd) as therapy for adult patients with platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancers expressing CDH6 previously treated with bevacizumab (Avastin), according to a press release from the developer, Merck.¹

The designation was granted based on results from a phase 1 trial (NCT04707248) that evaluated R-DXd in patients with renal cell carcinoma and ovarian cancer, and the ongoing phase 2/3 REJOICE-Ovarian01 trial (NCT06161025) that evaluated R-DXd in those with ovarian, peritoneal, or fallopian tube cancers.

Analyses of the phase 1 trial have been shared at the 2023 European Society for Medical Oncology, the 2024 Society for Gynecologic Oncology Annual meeting on Women’s Cancer, and the 2025 European Society for Medical Oncology Gynecological Cancers Congress.²

“Patients have limited treatment options once ovarian cancer becomes resistant to platinum-based chemotherapy, highlighting the urgent need for new medicines that can improve patient outcomes,” stated Ken Takeshita, MD, global head of Research & Development at Daiichi Sankyo, in the press release.¹ “The receipt of Breakthrough Therapy Designation represents an important step forward in our efforts to advance raludotatug deruxtecan as a novel medicine for patients with CDH6 expressing platinum-resistant ovarian, primary peritoneal, or fallopian tube cancers previously treated with bevacizumab.”

The Phase 1 Trial

This was a first-in-human trial that enrolled 179 patients in Asia and North America. In the subgroup analysis, 50 patients with ovarian cancer who were evaluable for efficacy evaluation via RECIST v1.1 were included.

As of the data cutoff date of July 14, 2023, the confirmed objective response rate (ORR) by investigator assessment was 46% (95% CI, 32%-61%), with 1 complete response, 22 partial responses, and 4 unconfirmed responses. The disease control rate (DCR) was 98%, and the median duration of response (DOR) was 11.2 months (95% CI, 3.0-not evaluable). The median progression-free survival (PFS) was 7.9 months (95% CI, 4.4-12.4). Notably, responses were reported in patients with varying levels of tumor CDH6 expression.

While the trial enrolled patients with renal cell carcinoma and ovarian cancer, the component of the trial including those with renal cell carcinoma was discontinued.

Eligible patients were at least 18 years old with an ECOG performance status of 0 or 1 and adequate organ function.³ Exclusion criteria included prior treatment with other CDH6-targeted agents, history or current presence of central nervous system metastases, multiple primary malignancies, and history of myocardial infarction.

In the ovarian cancer subgroup, R-DXd was administered in a range from 4.8 to 8.0 mg/kg.

In the first part of the study, the primary end point was to assess the safety and tolerability of increasing doses of R-DXd to determine the maximum tolerated dose and/or recommended dose for expansion. In the second part of the study, the primary end point was to evaluate the safety and efficacy of R-DXd. Additional end points included ORR, DOR, DCR, clinical benefit rate, PFS, dose-limiting toxicities, and adverse events.

Regarding safety, grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 51.7% of patients; the most common were anemia (18.3%), decreased neutrophil count (11.7%), decreased platelet count (5.0%), and fatigue (3.3%). Grade 5 interstitial lung disease events were observed twice in those at the 8.0 mg/kg dose, which has since been discontinued. TEAEs led to treatment discontinuations in 15% of patients.

The REJOICE-Ovarian01 Trial

This multicenter, randomized trial has an estimated enrollment of 710 patients with platinum-resistant, high-grade ovarian cancer, including primary peritoneal or fallopian tube cancer, who received at least 1 and no more than 3 prior systemic lines of anticancer therapy.^4,5

The phase 2 portion of the trial will evaluate the safety and tolerability of R-DXd at 4.8 mg/kg, 5.6 mg/kg, and 6.4 mg/kg to identify the recommended dose for the phase 3 portion of the trial. The primary end point of this portion of the trial was ORR assessed by blinded independent central review, and secondary end points were DOR, PFS, DCR, and overall survival (OS).

The phase 3 portion of the trial will evaluate the efficacy and safety of R-DXd compared with investigator’s choice of chemotherapy. The dual primary end points of this portion of the trial were ORR and PFS, and secondary end points were DOR, DCR, and OS.

References

1. Raludotatug deruxtecan granted breakthrough therapy designation by U.S. FDA for patients with CDH6 expressing platinum-resistant ovarian, primary peritoneal, or fallopian tube cancers previously treated with bevacizumab. News release. Merck. September 15, 2025. Accessed September 15, 2025. https://tinyurl.com/2yd6h7j6
2. Raludotatug deruxtecan continues to demonstrate promising clinical activity in patients with advanced ovarian cancer in early trial. News release. Daiichi-Sankyo. October 22, 2023. Accessed September 15, 2025. https://tinyurl.com/mt65nvaa
3. A study of DS-6000a in subjects with advanced renal cell carcinoma and ovarian tumors. ClinicalTrials.gov. Updated July 28, 2025. Accessed September 15, 2025. https://tinyurl.com/266hz6hx
4. A study of raludotatug deruxtecan (R-DXd) in subjects with platinum-resistant, high-grade ovarian, primary peritoneal, or fallopian tube cancer. ClinicalTrials.gov. Updated August 7, 2025. Accessed September 15, 2025. https://tinyurl.com/555u9u83
5. REJOICE-Ovarian01 phase 2/3 trial of raludotatug deruxtecan initiated in patients with platinum-resistant ovarian cancer. News release. Merck. April 3, 2024. Accessed September 15, 2025. https://tinyurl.com/mkzmd4xt