Sac-TMT Combo Produces Encouraging Activity in Pretreated Metastatic CRPC

"Overall, these findings support further development of sac-TMT plus pembrolizumab in [patients] with previously treated [metastatic] CRPC," according to the study authors.

Combining sacituzumab tirumotecan (sac-TMT; MK-2870/SKB264) with pembrolizumab (Keytruda) demonstrated promising activity and a manageable safety profile in a small cohort of patients with previously treated metastatic castration-resistant prostate cancer (CRPC), according to findings from cohort D of the phase 2 2870-002/SKB264-II-06 study (NCT05642780) presented in a poster session at the European Society for Medical Oncology (ESMO) Congress 2025.1

Among all evaluable patients (n = 46), a prostate-specific antigen (PSA) 50 (PSA50) response occurred in 39% (95% CI, 25%-55%). Of 19 with measurable disease at baseline, the confirmed objective response rate (ORR) was 47% (95% CI, 24%-71%), which included complete responses (CRs) in 5% and partial responses (PRs) in 42%. Data showed a disease control rate (DCR) of 90% (95% CI, 67%-99%).

Regarding patients who received sac-TMT at 4 mg/kg (n = 10) or 5 mg/kg (n = 36), the PSA50 response rates were 50% (95% CI, 19%-81%) and 36% (95% CI, 21%-54%), respectively; there were 4 and 15 patients from each group who had measurable disease at baseline. The study treatment produced a confirmed ORR of 75% (95% CI, 19%-99%) and 40% (95% CI, 16%-68%) at each dosing level, with respective DCRs of 100% (95% CI, 40%-100%) and 87% (95% CI, 60%-98%). In the 5 mg/kg group, 7% had CRs while 33% had PRs; all patients with a response after receiving 4 mg/kg of sac-TMT experienced PRs.

“In this analysis of [patients] with previously treated [metastatic] CRPC enrolled in the 2870-002/SKB264-II-06 study, the safety profile of sac-TMT plus pembrolizumab was manageable and consistent with the known safety profiles of the individual monotherapy components; no new safety signals were observed. Encouraging antitumor activity was observed with both doses of sac-TMT plus pembrolizumab,” lead study author Xiaojie Bian, MD, PhD, from the Department of Urology at Fudan University Shanghai Cancer Center and Department of Oncology at Fudan University Shanghai Medical College, wrote with coauthors in the poster.1 “Overall, these findings support further development of sac-TMT plus pembrolizumab in [patients] with previously treated [metastatic] CRPC.”

Investigators of this phase 2 study evaluated sac-TMT plus pembrolizumab among patients with select solid tumors. The trial included patients with recurrent or metastatic cervical cancer in cohort A, locally advanced or metastatic urothelial carcinoma in cohort B, recurrent ovarian cancer in cohort C, metastatic prostate cancer in cohort D, and advanced endometrial cancer in cohort E.2

In cohort D of the trial, patients 18 years and older with cytologically or histologically confirmed metastatic CRPC without small cell histology were assigned to receive sac-TMT at 5 mg/kg or 4 mg/kg intravenously once every 2 weeks plus pembrolizumab at 400 mg intravenously every 6 weeks. Other eligibility criteria for this cohort included having progression within 6 months of screening on or after 1 or 2 next-generation hormonal therapeutics and no more than 1 chemotherapy regimen, measurable lesions per modified RECIST v1.1 guidelines, and an ECOG performance status of 0 or 1.

The trial’s primary end points were safety based on adverse effects (AEs) and AEs leading to discontinuation as well as efficacy based on ORR and the PSA50 response rate, defined as the proportion of those with a PSA level decrease of at least 50% at 3 or more weeks apart. Secondary end points included DCR, duration of response, and radiographic progression-free survival.

Across the overall population, the median age was 67.5 years (range, 50-86), and most patients had an ECOG performance status of 1 (85%). Additionally, most patients had a TROP2 H-score of at least 200 (52%), a PD-L1 combined positive score of less than 1 (63%), bone-only metastases (52%), 2 prior lines of treatment (44%), and prior treatment with docetaxel (57%).

The median duration of therapy with sac-TMT was 9.3 months (range, 0.03-20.1) in the overall population, 15.8 months (range, 3.4-17.1) in the 4 mg/kg group, and 8.5 months (range, 0.03-20.1) in the 5 mg/kg group. The median duration of treatment with pembrolizumab in each respective group was 8.8 months (range, 0.03-20.1), 14.8 months (range, 2.9-16.6), and 7.7 months (range, 0.03-20.1).

Treatment-related AEs (TRAEs) occurred in 100% of the overall, 4 mg/kg, and 5 mg/kg populations. Additionally, 67%, 50%, and 72% had grade 3 or higher TRAEs; 65%, 60%, and 67% experienced TRAEs associated with treatment interruption; 26%, 10%, and 31% had TRAEs leading to dose reductions; and 17%, 10%, and 19% discontinued any study treatment due to TRAEs. One patient in the 5 mg/kg group died to a grade 5 treatment-related sepsis event.

In the 4 mg/kg and 5 mg/kg groups, respectively, the most common TRAEs of any grade included anemia (80% vs 81%), stomatitis (50% vs 53%), decreased appetite (50% vs 31%), decreased neutrophil counts (60% vs 22%), and decreased white blood cell counts (30% vs 31%). The most common grade 3/4 TRAEs included neutrophil count decreases (30%), anemia (20%), and white blood cell count decreases (10%) in the 4 mg/kg group as well as anemia (17%), neutropenia (17%), and stomatitis (11%) in the 5 mg/kg group.

References

1. Bian X, Jiang S, Goh JC, et al. Sacituzumab tirumotecan (sac-TMT) + pembrolizumab (Pembro) in metastatic castration-resistant prostate cancer (mCRPC): results from phase II MK-2870-002/SKB264-II-06 study. Presented at the European Society for Medical Oncology (ESMO) Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract 2421P.
2. SKB264 in combination with pembrolizumab in subjects with selected solid tumors. ClinicalTrials.gov. Updated October 14, 2025. Accessed October 30, 2025. https://tinyurl.com/2u49v648