custirsen (OGX-011) / Achieve Life Sciences - LARVOL DELTA

LBA02-09 EMBARK: A Phase 3 Randomized Study of Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in High-risk Biochemically Recurrent Prostate Cancer. (PubMed, J Urol) - P3 | "In pts with high-risk BCR, enza + ADT and enza mono demonstrated a statistically significant and clinically meaningful improvement in MFS vs pbo + ADT. The safety profile of enza was consistent with results from previous clinical studies."

Journal • Monotherapy • P3 data • Fatigue • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

External validation of a prognostic model for overall survival (OS) in men with metastatic castration-resistant prostate cancer(mCRPC). (ASCO 2019) - P3; "Background: We have previously developed and externally validated a prognostic model of OS in men with mCRPC treated with docetaxel (D), which included eight predictors: opioid analgesic use, ECOG performance status, albumin, disease site, LDH, hemoglobin, PSA, and alkaline phosphatase... Data from 5,790 mCRPC men randomized on 5 phase III trials were utilized to validate the prognostic model of OS: D +/- zibotentan (ENTHUSE), D +/- lenalidomide (MAINSAIL), D +/- dasatinib (READY), D+/- custirsen (SYNERGY), and tasquinimod/placebo))... This prognostic model for OS in men with mCRPC has been validated in a larger dataset, yields similar results across race, age and treatment groups. The model is robust and can be used to identify prognostic risk groups of patients for stratification and enrichment trials. Clinical trial information: NCT00626548"

Clinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

The multiple roles and therapeutic potential of clusterin in non-small-cell lung cancer: a narrative review. (PubMed, Transl Lung Cancer Res) - "By silencing CLU using Custirsen (OGX-011), a second-generation antisense oligonucleotide (ASO) that inhibits CLU production, not only could sensitized cells to chemo- and radiotherapy, also could decreased their metastatic potential. We will review here the extensive literature linking CLU to NSCLC, update the current state of research on CLU for better understanding of this unique protein and the development of more effective anti- CLU treatment."

Journal • Review • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CLU

Inhibition Lysosomal Degradation of Clusterin by Protein Kinase D3 Promotes Triple-Negative Breast Cancer Tumor Growth. (PubMed, Adv Sci (Weinh)) - "Finally, secreted CLU (sCLU) is found to be elevated in serums from TNBC patients and reduced in serum from TNBC murine models post OGX-011 and/or CRT0066101 treatment, suggesting serum sCLU is a promising blood-based biomarker for clinical management of TNBC. Taken together, this study provides a thorough molecular basis as well as preclinical evidences for targeting CLU pathway as a new promising strategy against TNBC via revealing PRKD3 as the key regulator of CLU in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CLU

Clusterin as modulator of carcinogenesis: A potential avenue for targeted cancer therapy. (PubMed, Biochim Biophys Acta Rev Cancer) - "More importantly, genetic and antisense mediated inhibition (OGX-011) of CLU enhances the anticancer potential of different FDA-approved chemotherapeutic drugs at the clinical level, improving patient's survival. In this review, we have discussed the detailed mechanism of CLU-mediated modulation of different cancer-associated signaling pathways. We have also provided updated information on the current preclinical and clinical findings that drive trials in various cancer types for potential targeted cancer therapy."

Journal • Review • Oncology • CLU

Secretory Clusterin AS A Novel Molecular-targeted for Inhibiting Hepatocellular Carcinoma Growth. (PubMed, Curr Med Chem) - "Abnormal hepatic sCLU expression should not only be a new diagnostic biomarker but also a novel promising target for inhibiting HCC growth."

Biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Custirsen (OGX-011) combined with cabazitaxel and prednisone versus cabazitaxel and prednisone alone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (AFFINITY): a randomised, open-label, international, phase 3 trial. (PubMed, Lancet Oncol) - P3; "We noted no survival benefit in men with metastatic castration-resistant prostate cancer with the addition of custirsen to cabazitaxel and prednisone treatment. Cabazitaxel and prednisone remains the standard of care for patients with metastatic castration-resistant prostate cancer progressing after docetaxel chemotherapy."

Journal • P1 data • P2 data • P3 data • Biosimilar • Pain • Prostate Cancer

Serum Free Methylated Glutathione S-transferase 1 DNA Levels, Survival, and Response to Docetaxel in Metastatic, Castration-resistant Prostate Cancer: Post Hoc Analyses of Data from a Phase 3 Trial. (PubMed, Eur Urol) - "This is the first study to externally validate the prognostic role of a circulating epigenetic biomarker in mCRPC. Further studies are needed to validate serum free mGSTP1 as a surrogate endpoint for clinical trials and as a potential clinical decision tool."

Biomarker • Journal • P3 data • Retrospective data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. (PubMed) - Lancet Oncol - P3; "Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone."

Journal • Biosimilar • Genito-urinary Cancer • Oncology • Pain • Prostate Cancer

Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): A phase 3, multicentre, open-label, randomised trial (The Lancet) - P3, N=1,022; SYNERGY (NCT01188187); OncoGenex Technologies; "Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone."

P3 data • Prostate Cancer

Prostate cancer custirsen trial fails to show improvement in survival (The Cancer Letter) - P3, N=630, 700; NCT01578655, NCT01630733; Sponsor: OncoGenex; "The phase III AFFINITY study failed to show a statistically significant improvement in overall survival for patients treated with custirsen in combination with cabazitaxel/prednisone compared to cabazitaxel/prednisone alone...The results were consistent with those observed in previous trials of custirsen in metastatic CPRC...ENSPIRIT trial has nearly completed enrollment and we believe there are likely a sufficient number of events to determine the effect of custirsen in NSCLC..."

Enrollment status • P3 data • Non Small Cell Lung Cancer • Oncology • Prostate Cancer

OncoGenex presents additional phase 3 SYNERGY analyses showing custirsen significantly reduced serum clusterin levels in metastatic prostate cancer patients; Low levels correlate with improved survival in those at increased risk for poor outcomes (Oncogenex Pharmaceuticals Press Release) - P3, N=357; SYNERGY; "...custirsen treatment significantly lowered serum clusterin (sCLU) levels from baseline in men with...(mCRPC)....sCLU reductions after custirsen treatment resulted in higher two-year survival rates in patients who were at increased risk for poor outcomes. Of those patients with lower sCLU levels, the data also showed a correlation to an overall survival benefit for custirsen-treated patients who were at increased risk for poor outcomes."

P3 data • Prostate Cancer

Phase III SYNERGY trial: Docetaxel +/- custirsen and overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and poor prognosis (ASCO 2015) - Presentation time: Saturday, May 30; 1:15 PM - 4:45 PM; Abstract #5009; P3, N=984; SYNERGY (NCT01188187); "The HR estimate for custirsen survival benefit was 0.73 (95% CI: 0.0589 to 0.902) for poor prognosis and 1.02 (95% CI: 0.760 to 1.37) for good prognosis. The poor prognosis group was analyzed separately for treatment effect (n = 492). The median OS was 17.0 m in the custirsen arm vs. 14.0 m in the control arm (stratified HR = 0.72, 95%CI: 0.579 to 0.892, P = 0.0026). PSA progression in the poor prognosis group also favored custirsen with a HR of 0.73 (95% CI: 0.589 to 0.907) for PCWG1 and 0.808 (95% CI: 0.633 to 1.031) for PCWG2."

P3 data • Prostate Cancer

OGX-011 and Docetaxel in Treating Women With Locally Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P2; N=15; Completed; Sponsor: NCIC Clinical Trials Group; N=42 ➔ 15

Clinical • Combination therapy • Enrollment change • Breast Cancer • Hematological Disorders • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

OGX-011 and Docetaxel in Treating Patients With Metastatic or Locally Recurrent Solid Tumors (clinicaltrials.gov) - P1; N=40; Completed; Sponsor: NCIC Clinical Trials Group; N=30 ➔ 40

Clinical • Combination therapy • Enrollment change • Bladder Cancer • Breast Cancer • Genito-urinary Cancer • Gynecologic Cancers • Hematological Disorders • Hormone Receptor Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Thoracic Cancer • Urothelial Cancer • CLU

Prostate cancer: Clustirsin fails to improve outcomes. (PubMed, Nat Rev Urol) - No abstract available.

Journal

Meta-analysis of efficacy and safety of custirsen in patients with metastatic castration-resistant prostate cancer. (PubMed, Medicine (Baltimore)) - "Safety assessments indicated custirsen were often associated with complications resulting from neutropenia (P < .001), anaemia (P < .001), thrombocytopenia (P < .001), and diarrhea (P = .002).Our meta-analysis shows that custirsen has no obvious effect on improving the OS of patients with mCRPC. Adverse reactions were more common among those patients treated with custirsen as compared to those treated with placebo."

Journal • Retrospective data

Clinical validation of circulating cytokines as markers of prognosis and response to docetaxel in men with metastatic castration-resistant prostate cancer. (ASCO-GU 2019) - "External validation cohort: Serum samples taken at BL and/or preC3 docetaxel in 430 men with mCRPC on phase III SYNERGY study (docetaxel +/- custirsen as 1st line chemotherapy in mCRPC with no OS benefit in the experimental arm). Adherence to a biomarker development pipeline provides level 2 evidence of the prognostic value of circulating MIC-1/GDF15 in men with mCRPC receiving docetaxel. A prospective biomarker led study is now necessary to establish clinical utility."

Clinical

Clinical validation of circulating cytokines as markers of prognosis and response to docetaxel in men with metastatic castration-resistant prostate cancer. (ASCO-GU 2019) - "External validation cohort: Serum samples taken at BL and/or preC3 docetaxel in 430 men with mCRPC on phase III SYNERGY study (docetaxel +/- custirsen as 1st line chemotherapy in mCRPC with no OS benefit in the experimental arm). Adherence to a biomarker development pipeline provides level 2 evidence of the prognostic value of circulating MIC-1/GDF15 in men with mCRPC receiving docetaxel. A prospective biomarker led study is now necessary to establish clinical utility."

Clinical