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More than 20 million men are surviving with prostate cancer (PCa) in the world, making it the highest cancer-surviving group. In addition, each year close to 1.5 million new cases are diagnosed with prostate cancer, and approximately 400,000 die of the disease. Prostate cancer is the world’s second most common cancer among men and accounts for approximately 14.2 per cent of new cancer cases in men. National Cancer Registry Programme (India) data indicated that prostate cancer is on the rise in Indian males. A report on prostate cancer in Lancet that prostate cancer “tsunami is coming” made big news around the world and was picked up by Forbes and other media. The projection of new cases of prostate cancer is 2.9 million by 2040.
Over 80 per cent of all prostate cancer are androgen receptor (AR)-positive, and androgen receptor will continue to be the dominant therapeutic target for this disease. Although androgen-dependent prostate cancer is manageable with surgery and chemical castration, it becomes debilitating once resistance to targeted therapies develops and prostate cancer advances to castration-resistant prostate cancer (CRPC). In CRPC, the disease progresses despite androgen depletion. Castration-resistant prostate cancer presents a broad spectrum of diseases. It varies widely in terms of progression, severity, and patient impact. androgen receptor splice variants (AR-SVs) have been identified as one of the important drivers of castration-resistant prostate cancer with none of the existing androgen receptor antagonists that bind to the canonical ligand binding domain (LBD) being effective against them. Thus, targeting, inhibiting, and degrading the AR-SVs will be important for next-generation castration-resistant prostate cancer therapeutics. Several AR-dependent mechanisms have been attributed to the development of castration-resistant prostate cancer and resistance to current treatments. Thus, these pathways need to be modulated by alternate approaches. There is little (if any) differentiation between the approved AR antagonists; they all bind competitively to the AR LBD and are susceptible to similar resistance mechanisms, leading to resistance development shortly after treatment initiation.
In recent years, several drugs such as Galeterone (a multi-targeted androgen receptor antagonist), EPI-506 (targets the AR and its splice variants), and EPI-7386 (targets androgen receptor splice variants) failed due to various reasons. Proteolysis Targeting Chimera (PROTAC), which are chimeric molecules that degrade the target protein by ubiquitination is also under evaluation for castration-resistant prostate cancer. The lead molecule from Arvinas, ARV-110, produced mixed results in the clinic. The above treatments for prostate cancer extend survival for most patients. However, roughly 30 per cent of tumors do not respond, and patients who initially respond often develop resistance. One of the primary reasons for treatment failure or relapse is a mutation of the receptor protein for androgens.
A new kid in the block for the treatment of castration-resistant prostate cancer is a small molecule AR and AR-SV degrader ONCT-534. The ONCT-534 is a dual-action androgen receptor inhibitor that has shown activity in prostate cancer models against unmutated and mutated androgen receptors. ONCT-534 was invented at the University of Tennessee Health Science Center (UTHSC) by a group led by lead inventors, doctors Ramesh Narayanan (professor and interim associate dean of research in the College of Medicine, and deputy director of UTHSC Center for Cancer Research) and Duane D. Miller (professor emeritus, College of Pharmacy) and out-licensed to Oncternal Therapeutics, San Diego, CA (Oncternal.com). ONCT-534 is the lead molecule identified from a library created at UTHSC that possesses unique properties. ONCT-534 binds to the non-canonical N-terminus domain that is expressed in both AR and AR-SV and degrades all androgen receptor isoforms. ONCT-534 is orally bioavailable and produced outstanding efficacy in many preclinical models. Toxicology studies demonstrated a large window of safety. In vitro and in vivo studies showed that ONCT-534 binds to the AR-AF-1 domain and inhibits transcriptional activity, inducts degradation of both androgen receptor full-length proteins and AR-SV proteins, including AR-V7, anti-tumor activity in castration-resistant prostate cancer and intact xenograft, and anti-tumor activity in AR-V7-positive tumor xenografts in castrated animals.
The US Food and Drug Administration (US FDA), designated ONCT-534 as a fast track development programme for the treatment of patients with relapsed or refractory metastatic castration-resistant (mCRPC) resistant to approve androgen receptor pathway inhibitors (ARPIs) in October 2023. A phase I/II clinical trial (ONCT-534-101 (NCT05917470)) aiming to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ONCT-534 in patients with advanced prostate cancer who have become resistant to standard therapies was recently completed. The phase I/II clinical trial was a multi-center, open-label study consisting of two phases: dose escalation (phase I) and dose expansion (phase II). The primary objective of phase I was to determine the maximum tolerated dose (MTD) and recommend phase II dose (RP2D) of ONCT-534. This phase involved administering escalating doses of the drug to small cohorts of patients to assess safety and identify any dose-limiting toxicities (DLTs).
The results from the clinical trial indicated that ONCT-534 was well-tolerated at various dose levels, with manageable side effects. Early signs of clinical activity were observed, including reductions in prostate-specific antigen (PSA) levels and partial tumor responses in some patients. Enumeration and biomarker analysis of circulating tumor cells showed promising effects on the expression of androgen receptor-regulated genes, and androgen receptor nuclear translocation in six additional patients. These findings suggest that ONCT-534 has the potential to provide therapeutic benefits for patients with castration-resistant prostate cancer who have exhausted other treatment options. Fifteen patients were treated with ONCT-534 once daily in six dosing cohorts and six patients received ONCT-534 BID. All doses were well tolerated, with no grade 3 or higher toxicities. Six of nine evaluable patients had a reduction in serum PSA, with one patient in a BID cohort demonstrating a greater than 50 per cent prostate-specific antigen reduction and a 16 per cent reduction in target lesions compared to baseline after four weeks of treatment. Circulating tumour cells biomarker analysis showed a promising reduction in androgen receptor-regulated genes and androgen receptor nuclear translocation. Circulating tumor cells analysis also showed that some patients who did not respond to ONCT-534 had neuroendocrine features, and androgen receptor independent disease subtype.
The phase I/II clinical trial of ONCT-534 represents a significant step forward in developing new treatments for castration-resistant prostate cancer. The promising preliminary results support further investigation into its efficacy and safety. ONCT-534 could offer a new therapeutic option for patients with advanced prostate cancer, improving their prognosis and quality of life.
Publications from the University of Tennessee also show that ONCT-534 and its sister molecule, UT-105, are efficacious in models of triple-negative breast cancer.
(Author is Director - Toxicology, PNB Vesper Life Science, Kochi, Kerala 682 011)
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