Experts explored the efficacy and safety of poly (ADP-ribose) polymerase (PARP) inhibitors and other targeted cancer treatments during the clinical trials plenary session Advances in Targeted Therapy on Monday, April 8, at the American Association for Cancer Research Annual Meeting 2024.

This session was chaired by Ryan B. Corcoran, MD, PhD, Mark J. Kusek Endowed Chair in Colorectal Cancer and associate professor of medicine at Harvard Medical School, and director of the Tucker Gosnell Center for Gastrointestinal Cancers at Massachusetts General Hospital Cancer Center. Registered Annual Meeting attendees can watch a recording of the presentations on demand through July 10, 2024, on the virtual meeting platform.

PARTNER trial: neoadjuvant olaparib in germline BRCA mutated (gBRCAm) breast cancer

Jean Abraham, PhD, director of the Cambridge Breast Cancer Research Unit at the University of Cambridge, presented results from the gBRCAm breast cancer cohort of the phase II/III PARTNER trial.

While PARP inhibitors (PARPi) have been used in many types of cancer, side effects have prevented their combination with chemotherapy to improve outcomes in gBRCAm breast cancer.

“One of the major problems has been the compounding bone marrow toxicity that we find when we bring together the PARP inhibitor and carboplatin-containing regimens,” Abraham said. However, preclinical studies suggested that a 48-hour gap between the two therapies could solve this problem. A research arm of the PARTNER trial tested this hypothesis.

Treatment with olaparib 48 hours after platinum-containing chemotherapy improved all survival endpoints, regardless of pathological complete response (pCR) status, compared with chemotherapy alone. One hundred percent of patients were alive at three years. The olaparib and platinum-containing chemotherapy regimen was well tolerated, with the need for a blood transfusion being the main issue.

PARTNER Trial: neoadjuvant olaparib in triple negative breast cancer (TNBC)

Karen Pinilla, MD, clinical research fellow and PhD candidate at the University of Cambridge, presented results from the triple negative breast cancer (TNBC) cohort of the PARTNER trial.

Some TNBC patients who are germline BRCA wildtype (gBRCAwt) may have other forms of homologous recombination deficiency, resulting in a BRCA-like phenotype. “We know from preclinical data that PARP inhibitors, in combination with DNA-damaging agents such as platinum, could have a synergistic effect,” said Pinilla. The PARTNER trial evaluated if gBRCAwt TNBC patients could benefit from PARP inhibition with olaparib in addition to platinum-containing chemotherapy.

Neoadjuvant olaparib plus platinum-containing chemotherapy did not improve pCR, event-free survival (EFS), or overall survival (OS), but patients who achieved a pCR had better EFS and OS. The safety profile was consistent with olaparib monotherapy with a slight elevation in grade 3 or higher adverse events.

KRYSTAL-1: adagrasib plus cetuximab in KRAS^G12C-mutated metastatic colorectal cancer (CRC)

Scott Kopetz, MD, PhD, professor and deputy chair for translational research in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, presented pooled phase I/II efficacy and safety data from the KRYSTAL-1 trial of adagrasib in combination with cetuximab in patients with KRAS^G12C-mutated metastatic CRC.

There is a need for more effective late-line regimens for metastatic CRC, Kopetz said. Targeting KRAS^G12C mutations, which occur in 3% to 4% of CRC cases and are associated with poor prognosis, may improve outcomes.

“Adagrasib is an irreversible inhibitor of KRAS^G12C with favorable properties that include dose-dependent pharmacokinetics, central nervous system penetration, as well as a long half-life,” Kopetz noted.

Adagrasib plus cetuximab demonstrated clinically meaningful antitumor activity and had a tolerable safety profile that was consistent with that of the drugs individually. Based on these positive findings, the phase III KRYSTAL-10 trial was initiated to evaluate second-line adagrasib plus cetuximab versus chemotherapy in metastatic CRC with KRAS^G12C mutations.

PETRA: saruparib in advanced solid tumors with BRCA1/2, PALB2, or RAD51C/D mutations

Timothy A. Yap, MBBS, PhD, professor and vice president of Clinical Development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center, presented the first-in-human, phase I/IIa trial results of saruparib (AZD5305) in patients with advanced solid tumors with BRCA1/2, PALB2, or RAD51C/D mutations.

Currently approved PARP inhibitors are dual PARP1/PARP2 inhibitors; however, only PARP1 inhibition is required for synthetic lethality in homologous recombination deficiency settings. “Therefore, saruparib was developed through rational design to be highly selective for PARP1, with increased potency and improved physicochemical properties versus all approved PARP inhibitors,” Yap said.

Saruparib has an optimal pharmacological profile, with a quick onset of action and higher pharmacological coverage than other approved PARP inhibitors. The PETRA trial found that 60 mg of saruparib once daily demonstrated deep and durable responses. Saruparib showed promising benefits in terms of objective response rate, duration of response, and progression-free survival with a favorable safety profile.