Mixed Results for Therapeutic Candidates for Platinum-Resistant Ovarian Cancer

Promising therapies for platinum-resistant ovarian cancer produced mixed results in separate trials.

The AKT inhibitor afuresertib failed to improve progression-free survival (PFS) when added to paclitaxel for patients with heavily treated advanced disease. An exploratory analysis suggested a potential benefit in a small subset of patients with phosphor (p)AKT-positive tumors.

On the other hand, the antibody-drug conjugate (ADC) DB-1305/BNT325, targeting TROP-2, led to objective responses in 41.4%, disease control in 82%, and a median PFS of 7.3 months in a small, heavily pretreated patient population.

Both studies were reported at the Society of Gynecologic Oncology (SGO) annual meeting in Seattle.

“Clearly, this was a definitive negative trial for the overall population,” said Thomas J. Herzog, MD, of the University of Cincinnati, who reported the afuresertib study. “However, the biomarker data is provocative, but remember, this is hypothesis-generating only, as it’s nonanalytic.”

The TROP-2 ADC “demonstrated encouraging durable efficacy and a manageable safety profile in patients with previously treated ovarian cancer,” said Maria Rubinstein, MD, of Memorial Sloan Kettering Cancer Center in New York City. “The data support further global clinical development.”

An ongoing study is evaluating DB-1305/BNT324 plus the anti-PD-L1/VEGF-A bispecific antibody, which has shown early efficacy in ovarian cancer, Rubinstein added.

Afuresertib did not demonstrate efficacy in an unselected population of patients with platinum resistant ovarian cancer, said SGO discussant B.J. Rimel, MD, of Cedars-Sinai Medical Center in Los Angeles. The analysis of the phosphor-AKT-positive subset yielded a “provocative signal.” Future studies of the AKT inhibitor should focus on biomarker-directed strategies.

TROP-2 is highly expressed in gynecologic cancers, and the target is the subject of intense investigation with no fewer than a dozen ADCs, said Rimel. The results with DB-1305/BNT324 are “exciting” and similar to results with datopotamab deruxtecan (Datroway) reported at the 2024 European Society for Medical Oncology meeting.

The DB-1305/BNT324 led to a concerning 40% rate of stage III stomatitis, which declined to 20% with a lower dose, Rimel continued. Interestingly, stomatitis occurred 11 times as often in patients who had partial response or stable disease as compared with progressive disease.

Signaling in the PI3K/AKT/mTOR pathway is often disrupted in cancers, including ovarian cancer, Herzog noted in his introduction. In particular, key downstream pathways are mediated by AKT.

Afuresertib is an oral pan-AKT inhibitor that reduces AKT activity in cancer cells and may resensitize the cells to platinum-taxane treatment. The PROFECTA-II/GOG-3044 trial tested the hypothesis that AKT inhibition improves in platinum-resistant ovarian cancer when an AKT inhibitor is combined with chemotherapy.

Eligible patients had received two to five prior lines of therapy for ovarian cancer, and disease relapse occurred within 6 months after completing the most recent treatment. Patients were randomized 2:1 to pacitaxel plus afuresertib or alone. The primary endpoint was PFS.

The primary analysis involving 150 patients showed a median PFS of 4.3 months with the combination and 4.1 months with single-agent paclitaxel (P=0.139). Median overall survival was numerically better with paclitaxel monotherapy (13.1 vs 11.2 months). Objective response rate (ORR) was numerically better with the combination (25% vs 18%) as was disease control (68% vs 57%).

A prespecified exploratory analysis of PFS in 37 biomarker-positive patients (pAKT >1) showed a median PFS of 5.4 months with the combination versus 2.9 months with paclitaxel alone, which translated into a 60% reduction in the PFS hazard (95% CI 0.12-1.00).

More than 60% of patients in the afuresertib arm had grade 3/4 drug-related treatment-emergent adverse events (TEAEs). Additionally, a third of patients randomized to the targeted agent had serious TEAEs, and 20.2% of patients in the treatment arm discontinued because of TEAEs versus 6.4% with single-agent paclitaxel. The most common TEAEs (any grade) were diarrhea (64.6%), anemia (54.5%), neutropenia (50.0%), fatigue (45.5%), and leukopenia (40.4%).

Rubinstein reported efficacy and safety from a phase I/II study of the TROP 2-targeted ADC, which includes a next-generation topoisomerase inhibitor. The trial included a total of 58 patients, 18 in the dose-escalation component of the study and 40 in the dose-optimization phase. Patients in the dose-optimization component had received as many as four prior lines of therapy and documented platinum resistance.

Across all doses of DB-1305/BNT325, the ORR was 41.4%, including 40%, 50%, and 35.7% for patients who received doses evaluated in the dose-optimization phase of the study. The disease control rate was 82.8% overall and 80-90% in the dose-optimization cohorts. The median duration of response was 7.3 months.

Among 30 patients who received the optimized dose, the most common treatment-related AEs were stomatitis (66.7%, 20% grade 3), nausea (36.7%, 3.3%), anemia (30%, 6.7%), weight loss (20.0%), constipation (20.0%), and vomiting (20.0%, 3.3%).

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