Dr Yap on the Continued Investigation of Saruparib in Advanced Solid Tumors

Timothy Yap, MBBS, PhD, FRCP, medical oncologist, physician-scientist, professor, Department for Investigational Cancer Therapeutics (Phase I Program), Department of Thoracic/Head and Neck Medical Oncology; vice president, head, clinical development, Therapeutics Discovery Division; associate director, translational research, Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, discusses next steps for investigating saruparib (AZD5305) in patients with advanced solid tumors, including prostate cancer, that harbor genetic mutations.

Future investigations of saruparib involves will expand across various cancer types and genetic mutations, Yap begins. This drug’s potential goes beyond its current scope, necessitating comprehensive exploration in diverse oncological settings, he says. Saruparib is currently being evaluated in the phase 3 EvoPAR-PR01 clinical trial (NCT06120491) in patients with prostate cancer, where it will be used in combination with new hormonal agents, Yap explains, adding that other studies are also planned to further understand and establish the drug’s efficacy and safety profiles.

, the most common genetic alterations observed were 

 mutations, he continues. As expected, these mutations were prominent in the patient population, but differentiating the efficacy of saruparib across these mutations has proven challenging, according to Yap. This is an area that will require more in-depth investigation in future studies, Yap elucidates. Understanding these differences is crucial for tailoring treatments to individual genetic profiles and optimizing therapeutic outcomes, he notes.

Saruparib is a first-in-class PARP1 selective inhibitor, 

first-generation PARP1 and PARP2 inhibitors

. This new class of PARP1 selective drugs holds the promise of significantly enhanced efficacy, Yap expands. The rationale behind this optimism lies in the selective targeting mechanism of these agents, which potentially offers a higher therapeutic index, Yap notes. Saruparib has been associated with a promising safety profile in preliminary studies, alongside favorable pharmacokinetic and pharmacodynamic characteristics, he concludes.

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Timothy Yap, MBBS, PhD, FRCP, discusses next steps for investigating saruparib in advanced solid tumors with genetic mutations, including prostate cancer.

Dr Yap on the Investigation of Saruparib in Solid Tumors

Timothy Yap, MBBS, PhD, FRCP, medical oncologist, physician-scientist, professor, Department for Investigational Cancer Therapeutics (Phase I Program), Department of Thoracic/Head and Neck Medical Oncology; vice president, head, clinical development, Therapeutics Discovery Division; associate director, translational research, Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, discusses the rationale for investigating saruparib (AZD5305) in patients with advanced solid tumors and genetic mutations.

Currently, there are 4 approved PARP inhibitors in clinical use that have demonstrated effectiveness and benefits for patients with cancer. However, these inhibitors are associated with a range of adverse effects (AEs), including fatigue, myelosuppression, and gastrointestinal issues, Yap begins. Given these AEs, there is a significant need to develop drugs that maintain high efficacy with minimal AEs, he states.

All currently approved PARP inhibitors target both PARP1 and PARP2 and act as trappers of these enzymes. The hypothesis driving the development of saruparib is that selectively inhibiting PARP1, without affecting PARP2, could achieve the desired therapeutic effects with fewer AEs, Yap continues. Saruparib is a first-in-class selective PARP1 inhibitor.

The clinical development of saruparib was undertaken through the phase 1/2a PETRA trial (NCT04644068), he expands. The trial consists of a dose-escalation phase followed by a dose-optimization expansion phase. During the dose-escalation phase, patients with breast, ovarian, prostate, and pancreatic cancers were enrolled, Yap details.

The trial was designed with flexible hemoglobin requirements and explored saruparib doses ranging from 10 mg to 140 mg administered once daily. This study approach aimed to determine the optimal dose of the agent that balances efficacy and safety for further clinical development, he explains. By focusing on a highly selective PARP1 inhibitor such as saruparib, researchers hope to provide a new therapeutic option that offers significant benefits with fewer AEs compared with existing PARP inhibitors, Yap concludes.

Timothy Yap, MBBS, PhD, FRCP, discusses the rationale for investigating saruparib in advanced solid tumors, such as prostate cancer with genetic mutations.

Dr Yap on Saruparib in BRCA1/2+, PALB2+, or RAD51C/D+ Advanced Solid Tumors

Timothy Yap, MBBS, PhD, FRCP, medical oncologist and physician-scientist; professor, Department for Investigational Cancer Therapeutics (Phase I Program), Department of Thoracic/Head and Neck Medical Oncology; vice president, head of clinical development, Therapeutics Discovery Division; and associate director of translational research, Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, discusses safety and efficacy data from the phase 1/2a PETRA trial (NCT04644068) investigating the first-in-class PARP1 inhibitor saruparib (AZD5305) as a treatment for patients with advanced solid tumors harboring 

Part A of the first-in-human study included patients with HER2-negative breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer who had not received more than 1 prior PARP inhibitor. Part B1 consisted of patients with HER2-negative breast cancer who were naive to PARP inhibitors; however, there was no limit on prior chemotherapy lines in the metastatic setting for these patients.

In part A, saruparib was administered at doses ranging from 10 mg to 140 mg once daily. In part B, the PARP1 inhibitor was given at 20 mg, 60 mg, or 90 mg once per day.

 showed that patients with HER2-negative breast cancer treated with 20 mg of saruparib in part B1 experienced a median best change in tumor size of –22.1% (range, –91.2% to 133.3%), an overall response rate (ORR) of 35.7% (80% CI, 23.5%-49.6%), and a median progression-free survival (PFS) of 4.6 months (80% CI, 3.7-5.4). In patients treated with 60 mg of the PARP1 inhibitor, the median best change in tumor size was –34.6% (range, –100% to 43.2%), the ORR was 48.4% (80% CI, 35.7%-61.3%), and the median PFS was 9.1 months (80% CI, 5.7-9.3).

Yap explains that treatment was generally well tolerated, and the majority of adverse effects were grade 1 or 2. He notes that rates of dose reductions, dose interruptions, and treatment discontinuations were lower than historical data for first-generation PARP inhibitors.

Significant pharmacodynamic effects were observed with over 90% PARP1 inhibition in both peripheral blood mononuclear cells and tumor biopsies, Yap says.

On top of the responses observed in part B1 of the study, responses were generated during dose escalation across all dose levels. These findings informed the decision to proceed to dose optimization in patients with HER2-negative breast cancer, he adds.

Timothy Yap, MBBS, PhD, FRCP, discusses data for saruparib in harboring BRCA1/2, PALB2, or RAD51C/D mutations.
 


Timothy Yap, MBBS, PhD, FRCP, medical oncologist, physician-scientist, associate professor, Department for Investigational Cancer Therapeutics, Department of Thoracic/Head and Neck Medical Oncology, medical director, Institute for Applied Cancer Science, associate director, Translational Research, Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, discusses the rationale for the ongoing phase 1b/2 SEASTAR trial in advanced solid tumors.

The open-label, multi-arm study will evaluate the efficacy, safety, and pharmacokinetics of the PARP1/2/3 inhibitor rucaparib (Rubraca) in combination with lucitanib or sacituzumab govitecan-hziy (Trodelvy) in patients with advanced or metastatic solid tumors. 

Currently, the phase 2 portion of the trial is enrolling patients into 2 arms. The first arm is testing rucaparib with lucitanib, an investigational VEGFR/FGFR TKI, in patients with 

The second arm is evaluating rucaparib in combination with the antibody-drug conjugate sacituzumab govitecan in patients with metastatic triple-negative breast cancer, advanced/metastatic urothelial carcinoma, or relapsed ovarian cancer. 

Rucaparib is currently approved as monotherapy for the treatment of patients with 

-mutant metastatic castration-resistant prostate cancer and as maintenance therapy for patients with recurrent ovarian cancer, concludes Yap. 

Timothy Yap, MBBS, PhD, FRCP, discusses the rationale for the ongoing phase 1b/2 SEASTAR trial in advanced solid tumors.  



Timothy Yap, MBBS, PhD, FRCP

Articles

Dr Yap on the Continued Investigation of Saruparib in Advanced Solid Tumors

Dr Yap on the Investigation of Saruparib in Solid Tumors

Dr Yap on Saruparib in BRCA1/2+, PALB2+, or RAD51C/D+ Advanced Solid Tumors

Dr. Yap on the Rationale for the SEASTAR Trial in Advanced Solid Tumors