AstraZeneca has punted a pair of early-phase prostate cancer programs as part of its quarterly pipeline clearout.
The drugmaker axed one asset, AZD9750, in response to pharmacokinetic (PK) and pharmacodynamic (PD) data. AZD9750 is an orally bioavailable androgen receptor (AR) degrader that AstraZeneca took into the clinic in January. Having initially expected to treat 300 patients across the phase 1/2 study, AstraZeneca stopped recruiting patients into the trial early this month after enrolling six participants.
AstraZeneca designed the drug candidate to address the limitations of AR pathway inhibitors, such as Pfizer's prostate cancer drug Xtandi. While cancer cells can develop resistance to AR pathway inhibitors, preclinical tests found AZD9750 degraded mutant and amplified forms of the receptor.
The drugmaker optimized the molecule’s oral bioavailability in rodents. However, PK/PD data prompted AstraZeneca to scrap development of the drug candidate shortly after starting tests in prostate cancer patients.
Another prostate cancer program, AZD8359, joined the AR degrader on AstraZeneca’s scrapheap. Citing "strategic" reasons, the Big Pharma ended development of AZD8359 months after starting a first-in-human trial.
AZD8359 is a T-cell engager targeting STEAP2, a prostate-associated surface antigen. The drug candidate is biased toward CD8-positive, rather than CD4-positive, T cells. The design could cut the risk of cytokine release syndrome and off-tumor activity, which can limit dosing of T-cell engagers. In vitro, AZD8359 killed tumor cells while reducing cytokine release by 40% compared to a conventional T-cell engager.
Buoyed by the preclinical findings, AstraZeneca started a phase 1/2 trial in May. The clinical trial was supposed to enroll 42 people with metastatic prostate cancer and finish late next year. Yet, AstraZeneca removed the program from its pipeline in its third-quarter earnings update.
The prostate cancer programs were two of the four early-phase assets that AstraZeneca culled this quarter. The company also ended work on AZD2962, an IRAK4 inhibitor in development in hematological malignancies. IRAK4 is a long-standing target of interest in cancer and inflammatory diseases across the biopharma industry. Pfizer and Gilead are among the companies to take IRAK4 inhibitors into the clinic.
AZD8421, a CDK2 inhibitor, is the fourth asset canned by AstraZeneca. This month, the company ended enrollment early in a phase 1/2a study that began in 2023 to test the drug candidate in solid tumors. Having aimed to enroll 564 patients, AstraZeneca closed the study to new participants after recruiting 55 subjects.
The drug candidate emerged from AstraZeneca's efforts to overcome the limitations of first-generation CDK2 inhibitors, which suffer from toxicity that is potentially related to a lack of selectivity. Through superior selectivity for CDK2 over CDK1, AZD8421 was designed to reduce toxicity and more precisely target aberrant cell cycle progression and resistance mechanisms.