Researchers report promising results from four clinical trials targeting the DNA damage response and KRAS

Patients with recurrent endometrial cancers currently have no good alternatives if first-line therapy fails, but triple therapy with olaparib, cyclophosphamide, and metformin may help.

Benoit You
Benoit You, MD, PhD

The combination showed good results in heavily pretreated patients in the ENDOLA trial, an open-label phase I/II trial of the triple combination, according to Benoit You, MD, PhD, Hospices Civils de Lyon, Lyon, France.

You was one of three researchers to present recent clinical trial results on Sunday, April 10, during the plenary session Clinical Trials Targeting the DNA Damage Response and KRAS. The session can be viewed on the virtual platform by registered meeting participants through July 13, 2022.

“There is an enormous need for innovative approaches beyond standard first-line treatment, and we have a very strong rationale to combine these three drugs,” You said.

Recurrent endometrial cancers exhibit frequent defective DNA repair, including homologous recombinations that can be treated with both PARP inhibition (olaparib) and alkylating chemotherapy (cyclophosphamide), he explained. Recurrent disease also exhibits frequent alterations of PI3K-AKT-mTOR and IGFR pathways, which is inhibited by metformin.

The ENDOLA trial enrolled 35 patients at six French centers. The median patient age was 69 and more than half were previously treated with at least four lines of therapy.

Phase I explored safety, adverse events, and a recommended phase II dose. Doses ranged from 150 mg to 300 mg BID olaparib plus 50 mg QD metronomic cyclophosphamide and 50 mg TID metformin over six weeks. Olaparib 300 mg was selected as the recommended phase II dose.

Phase II assessed safety, clinical outcomes, and exploratory biomarkers.

The objective response rate (ORR) across the two phases was 20.8 percent, the disease control rate (DCR) was 66.6 percent, and 61.5 percent of patients showed no progression at 10 weeks. Median progression-free survival (PFS) was 5.1 months, and 38.7 percent of patients had dose reductions for treatment-related adverse events.

“We can see this in clinical practice with a certain number of patients who do not tolerate PARP inhibition,” You said. “Only two patients, 6.4 percent, discontinued treatment for toxicity.”

Timothy A. Yap, MBBS, PhD
Timothy A. Yap, MD, PhD

Follow-up results on elimusertib in advanced solid tumors suggest dose schedule change
Phase I results for elimusertib, a selective inhibitor of ataxia telangiectasia and Rad3-related (ATR), published in 2021, showed good antitumor activity in advanced solid tumors. Phase Ib results in 143 patients show similarly positive effects, reported Timothy A. Yap, MD, PhD, University of Texas MD Anderson Cancer.

Trial participants had a mix of advanced prostate, colorectal, gynecologic, and breast tumors. There were no complete responses and 3.6 percent had partial responses (PR). The DCR was 58.7 percent and 34.8 percent of patients showed clinical benefit.

Phase Ib also suggested that an alternative dosing schedule of three days on/11 days off can minimize more serious treatment-related hematologic adverse events, Yap reported. The initial schedule is three days on/four days off.

“Hematologic adverse events on the 3/4 schedule were reversible and manageable with dose interruptions or reductions and supportive measures, but we had dose reductions in 53 patients and eight patients discontinued,” Yap said. “The 3/11 schedule had only five treatment-related dose reductions and no discontinuations. The alternative dosing schedule needs to be evaluated in future studies.”

First PARP1 inhibitor trial shows strong results
Yap also presented results from PETRA, a first-in-human and first-in-class trial of a PARP1-selective inhibitor. The study agent, AZD5305, showed improved safety results compared to first-generation PARP inhibitors that target both PARP1 and PARP2, he said.

The most clinically important adverse events with PARP1/2 inhibitors are hematologic toxicities, Yap said. Preclinical studies show that PARP2 is essential for erythropoiesis and PARP1 inhibition alone is sufficient for antitumor efficacy. AZD5305 is selective for PARP1.

The global phase I/II PETRA study used six doses of AZD5305 ranging from 10 mg to 140 mg in patients with progressive ovarian, HER2-breast, pancreatic, or prostate cancer. All patients had a loss-of-function mutation in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. The first patient was treated in November 2020 and the trial is ongoing. Data cutoff was Feb. 22, 2022.

The most commonly reported adverse events were nausea, anemia, neutropenia, and thrombocytopenia. There were no treatment discontinuations and two dose reductions. First-generation PARPi trials reported dose reductions in up to 53 percent of participants with a 14 percent discontinuation rate.

“Responses were observed starting at the lowest dose levels and across all tumor types, mutation types, and independent of prior PARPi use. Treatment is ongoing in 19 patients after at least 16 weeks,” Yap said.

Grace K. Dy, MD
Grace K. Dy, MD

Two-year analysis of CodeBreaK 100
An initial analysis of the phase II CodeBreaK 100 study of sotorasib, a selective KRAS inhibitor, showed an ORR of 37.1 percent, median PFS of 6.8 months, and median OS of 12.5 months after a median follow up of 15.3 months. After 25 months of follow up, a second analysis showed an ORR of 40.7 percent, PFS of 6.3 months, and two-year OS of 32.5 percent, reported Grace K. Dy, MD, Roswell Park Comprehensive Cancer Center.

The median duration of response in the two-year analysis was 12.3 months and 84 percent of patients had disease control, she said.

The global trial enrolled 172 patients with locally advanced or metastatic KRASG12C-mutated non-small cell lung cancer with at least one prior systemic therapy. The majority of study participants, 92.5 percent, had undergone prior platinum-based chemotherapy and 90.2 percent had prior anti-PD-L1 treatment, while 82.8 percent had been treated with both therapies.

About a quarter of patients experienced a PFS of 12 months or longer, Dy reported. “Long-term clinical benefit was seen across the range of KRAS allele frequency, PD-L1 tumor score, and with other co-mutations.”

Treatment-related adverse events were largely unchanged with one new grade III adverse event, hemolytic anemia. There were no fatal TRAEs and no TRAE leading to discontinuation after the first year, Dy reported.

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Register Today for the AACR Annual Meeting 2024

The AACR Annual Meeting 2024 is underway in San Diego, but registration is still available. Both in-person and virtual registration options include access to live sessions, Q&A, networking, CME/MOC credits, on-demand access to sessions through July 10, 2024, and more.