In the first opportunity for industry watchers to compare the two approved TROP2 antibody-drug conjugates side by side in separate global phase 3 trials in the same disease setting, it’s AstraZeneca and Daiichi Sankyo’s Datroway that appears to take the upper hand over Gilead Sciences' Trodelvy.
Datroway reduced the risk of death versus chemotherapy by 21% as a first-line treatment for patients with metastatic triple-negative breast cancer (TNBC) who are not candidates for immunotherapy, according to results from the phase 3 Tropion-Breast02 trial. The result was statistically significant.
The data are being shared this weekend at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin.
In another Sunday ESMO data reveal, Trodelvy was not yet able to claim a statistically significant overall survival benefit in the Ascent-03 study in the same first-line TNBC setting among patients who are not eligible for anti-PD-1/L1 treatments. The OS outcome, while immature, is trending in “the right direction” for Trodelvy, Gilead Chief Medical Officer Dietmar Berger, M.D., Ph.D., said in an interview with Fierce Pharma.
In both studies, fewer patients discontinued ADC treatments due to adverse events than did those in the control groups.
The Ascent-03 trial is still positive, because it met the primary endpoint of progression-free survival (PFS), showing Trodelvy pared down the risk of progression or death by 38% versus chemo. The median PFS was 9.7 months for Trodelvy versus 6.9 months for chemo.
The magnitude of Trodelvy’s PFS benefit was smaller than Datroway’s by a cross-trial comparison. In Tropion-Breast02, treatment with Datroway yielded a 43% reduction in the risk of progression or death. The median PFS for Datroway was 10.8 months versus 5.6 months for chemo.
The two TROP2 studies have many similarities. They’re targeting the same disease indication, and they both enrolled more than 600 but less than 650 patients. The Gilead trial was launched only two months behind the AZ/Daiichi one in the summer of 2022.
But cross-trial comparisons should be done with caution, because they don't account for differences in patient characteristics. The studies’ differing median PFS numbers in the control arms show the nuances often behind such comparisons.
In one important trial difference, Gilead’s Ascent-03 study allowed patients in the control arm to receive Trodelvy upon first-line progression because the drug has been approved in the U.S. as a second-line TNBC therapy. The crossover rate was high, Berger noted in an interview with Fierce Pharma.
“With more than 80% of crossover, there will be an impact [on overall survival],” Berger said, later adding that, “I feel in the community, people do understand that there are differences in study design, and they also see the benefit that Trodelvy has for their patient population.”
Because of that crossover design, Gilead conducted its trial in regions where Trodelvy is readily available, which Berger pointed out as another difference versus the Datroway trial.
By comparison, Datroway does not have a TNBC indication on its label. In Tropion-Breast02, for Datroway versus chemotherapy, 65% versus 72% of patients received any subsequent therapy in any treatment line, including 14% versus 30% who received a subsequent TROP2 ADC, according to a Daiichi spokesperson.
However, while subsequent therapy crossover may explain the OS results, it cannot explain another weak point in Trodelvy’s data set. The first-in-class TROP2 ADC surprisingly showed almost no advantage over chemo when it came to inducing a tumor response. The objective response rate was 48% with Trodelvy and 46% with chemotherapy.
The small ORR difference came in contrast to what Trodelvy showed in the Ascent trial in patients with previously treated TNBC. In that phase 3, Trodelvy’s ORR was 31%, notably better than chemo’s 4%. But it looks more similar to results in the Ascent-04 trial, which linked Trodelvy in combination with Merck & Co.’s Keytruda to a 60% ORR in first-line PD-L1-positive TNBC, versus 53% for Keytruda and chemo.
At that time, Leerink Partners analysts said they were reminded by an expert that “ORR is an important outcome with direct clinical meaningfulness in 1L TNBC, given the degree of symptoms the disease causes and visceral involvement,” according to a June 2 note.
Datroway appeared to be differentiated on ORR, as well, with a 62.5% rate versus chemo’s 29.3% in Tropion-Breast02.
Susan Galbraith, Ph.D., AZ’s oncology R&D chief, attributed Datroway’s strong efficacy to its ADC construct, specifically its linker-payload technology that allows the drug to have a bystander effect in which neighboring cancer cells that do not express the antigen targeted by the ADC are also killed by the cytotoxic payload.
Berger acknowledged that the benefit observed with Trodelvy “comes largely from duration of response.” Here, again, Trodelvy didn’t show an advantage over Datroway by a cross-trial comparison. The median duration of response was 12.2 months for the Gilead med versus 12.3 months for the AZ/Daiichi drug in their separate trials. The control arms’ numbers were similar, at 7.2 months and 7.1 months, respectively.
While Gilead hopes the OS results will eventually reach statistical significance, Berger said it’s difficult to speculate, especially given the high crossover rate.
For now, Gilead hopes the combination of the Ascent-03 readout and similarly positive results from the Ascent-04 study in first-line PD-L1-positive TNBC—as well as doctors’ familiarity with Trodelvy in its more than five years on the TNBC market—could give it a boon. Gilead is speaking with regulators about the results of both trials, and PFS is an approvable endpoint without an OS detriment, Berger said.
“Having very similar data in Ascent-03 and Ascent-04 is really giving us a possibility to have Trodelvy as kind of a backbone for therapy in first-line triple-negative breast cancer,” Berger said.
But Ken Keller, head of Daiichi’s global oncology business, argued that the huge success of the Japanese pharma’s other DXd-based ADC, Enhertu, could give Datroway a halo effect.
How long Gilead’s drug can maintain its lone standing as the only drug with positive data in both PD-L1-negative and PD-L1-positive first-line TNBC remains to be seen.
In its most recent pipeline update, AZ said it expects its Tropion-Breast05 trial for Datroway—either by itself or in combination with Imfinzi—in PD-L1-positive TNBC will read out in 2026 or beyond. Between the two TNBC subgroups, about 70% of patients are not eligible to receive a PD-1/L1 inhibitor.
Keller argued that Trodelvy’s possible initial differentiation with a broad TNBC indication across PD-L1 spectrum might not be too big a problem for Datroway, because doctors are still going to test for PD-L1 status.
“There is a comfort right now with Trodelvy. It has made a big difference for patients. I think it’s a drug that people hold in good regard. And so there’s always an inertia effect,” Keller said. “But again, I do think there is a halo for these DXd ADCs that I think will help us too.”
Meanwhile, AZ and Daiichi are looking to move even earlier into the TNBC treatment sequence. With Tropion-Breast03, the pair is testing Datroway as an adjuvant treatment in patients with stage 1 to 3 TNBC with residual invasive disease at surgical resection following neoadjuvant treatment.
Editor's Note: The story has been updated to remove an ORR data point from another phase 2 clinical trial of Datroway.