Orion Pharma’s ODM-208’s promising antitumor activity in heavily pre-treated mCRPC patients with AR LBD mutation

Prostate cancer is the second most frequently diagnosed cancer in men. There are no initial or early symptoms in most of the cases. Still, late symptoms may include fatigue due to anemia, bone pain, paralysis from spinal metastases, and renal failure from bilateral ureteral obstruction. According to the Cancer Treatment Centers of America (CTCA), more than 99% of prostate cancers are adenocarcinomas, which develop in the gland cells. It is common in men 50–64 years and over age 65; however, it can occur in men younger than 50 years. As per Delveinsight’s estimates, there are approximately 143,000 treatment-eligible Castration-Resistant Prostate Cancer (CRPC) patients in the United States in 2022, this includes both metastatic (mCRPC) and non-metastatic (nmCRPC) patients. 

Mutations that occur in the LBD in response to AR pathway inhibitors are one mechanism through, which therapeutic resistance arises. Surprisingly, while these mutations are absent in nonmetastatic castration-sensitive patients , they are enriched in heavily treated metastatic castration-resistant prostate cancer. As per ongoing research, these mutations have been previously correlated with overall and progression-free survival (PFS) in the post-docetaxel, but not in the treatment-naive space. Furthermore, their detection in mCRPCand absence in localized disease suggest that their emergence is a consequence of androgen deprivation therapy (ADT) treatment-acquired resistance.

ODM-208 is a complete blocker of steroid biosynthesis that suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signaling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). During treatment, the patients receive hormone replacement therapy to ensure sufficient adrenal function. Orion was the first pharmaceutical company to develop a drug using this mechanism. The study currently investigates the safety and tolerability of the drug prototype in prostate cancer patients, but Orion's plans include studying the molecule in the treatment of breast cancer patients as well. Moreover, ODM-208 has potential efficacy for those cancers that have become resistant to the standard hormonal treatments, giving it a reason to widen its horizon in breast cancer treatment as well. The company is evaluating this trial in collaboration with Merck for the treatment of patients with mCRPC.

In the first quarter of 2021, Orion started a clinical Phase II study for the development of a new type of selective hormone synthesis inhibitor (CYP11A1 inhibitor) for castration-resistant prostate cancer. In preclinical studies, the molecule (ODM-208) was found to inhibit the growth of cancer cells. Additionally, it was also effective for hormonal cancers that have become resistant to conventional hormonal cancer treatments. In February 2022, the company announced the results from an ongoing Phase I/II CYPIDES Trial of ODM-208 presented at ASCO-GU. According to the results, around 32% of the patients achieved a PSA (prostate-specific antigen) decrease of ≥50%. Of patients with AR LBD mutation (17), 68% achieved a PSA decrease of ≥50%. Moreover, prolonged treatment responses were observed especially in patients with AR LBD mutation. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 14 (32%) patients experienced severe adrenal insufficiency despite the replacement therapy requiring further adrenal supplementation after which the ODM-208 treatment commonly continued. Non-adrenal adverse events were unremarkable.

With the study's ongoing data cutoff date of July 25, 2022, the drug achieved manageable adrenal suppression which was the main concern for this Phase II study. As in the Phase I trial, a high proportion of men were hospitalized with adrenal insufficiency at some time during ODM-208 treatment at higher dose levels. That’s why the dose level was reduced to 5mg-BID in the Phase II study. Moreover, all these patients were selected as having evidence of AR-LBD mutation+ based on liquid biopsy. In addition to that, unmeasurable steroid hormone levels were achieved in almost all patients, and 53% of patients achieved a serum PSA reduction of at least 50% from the baseline concentration. 

In terms of safety profile, less than 7% of patients were having adrenal insufficiency, with Grade ≥3AE’S occurring in 67% of patients. Furthermore, around 4 patients withdrew due to adverse events, and 6 death occurred. Based on these findings, the administration of ODM-208 to heavily pre-treated mCRPC patients with AR LBD mutation was highly effective in blocking the production of steroid hormones and showed promising antitumor activity. Therefore, it can be anticipated that ODM-208 can be a promising treatment option in this patient pool.

*AR LBD- androgen receptor (AR) ligand-binding domain (LBD)

Get more detailed insights, at: Metastatic castration-resistant Prostate Cancer (mCRPC) Market, Metastatic Hormone Refractory Prostate Cancer Market, Ovarian Cancer Market, Pancreatic Cancer Market, ER positive HER2 negative Breast Cancer Market, and others