seviteronel (INO-464) / Innocrin - LARVOL DELTA

4CAST: Seviteronel in Combination With Chemotherapy in Androgen-receptor Positive Metastatic Triple-negative Breast Cancer (clinicaltrials.gov) - P1/2 | N=65 | Recruiting | Sponsor: St Vincent's Hospital, Sydney | Phase classification: P1b ➔ P1/2 | Trial completion date: Dec 2024 ➔ Dec 2027 | Trial primary completion date: Jul 2024 ➔ Jul 2026

Phase classification • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • HER-2 • PGR

State-gating cancer to prevent chemotherapy-resistance (AACR 2025) - P1b | "Seviteronel, a dual CYP17 lyase and AR inhibitor, faithfully mimics genetic AR ablation and is the most effective AR inhibitor in combination with chemotherapy...These data provide proof-of-concept for AR inhibition as a 'state-gating' strategy to lock cancer cells in therapy-sensitive states and prevent the emergence of chemotherapy-resistance in TNBC. This paradigm may be widely applicable to other cancers."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CYP17A1

Targeting androgen receptor to prevent cell state plasticity and chemotherapy resistance in triple-negative breast cancer (LCC 2025) - P1b | "Using extensive pre-clinical models, we showed that the dual CYP17 lyase/AR inhibitor seviteronel effectively sensitized TNBC to chemotherapy, through concurrent inhibition of AR and MYC signalling, coupled with the suppression of the PI3K/AKT/mTOR pathway. In contrast, abiraterone and enzalutamide, inadvertently activated these oncogenic signalling, reducing their effectiveness in TNBC...Early evidence of clinical efficacy led to a Phase 2 expansion study currently underway. Our work represents a significant step toward addressing the clinical challenge of targeting aggressive TNBC and developing effective treatment options to abrogate resistance across a range of AR-positive cancer types."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • CYP17A1 • HER-2

Exploring and targeting the androgen receptor pathway in glioblastoma (LCC 2025) - "Proliferation and tumoursphere formation were inhibited by enzalutamide, an AR antagonist, but more so by drugs that inhibit CYP17A1 and AR, abiraterone and seviteronel...However, seviteronel combined with temozolomide or radiotherapy did not extend survival compared to either treatment alone. Conclusions AR is expressed in a majority of glioblastoma samples. Targeting AR with existing brain-penetrant drugs is being further explored in animal experiments, as is the assessment of AR as a predictive or prognostic biomarker in this deadly disease."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • ZEB1

Exploring the role of androgen receptor signaling in glioblastoma in an orthotopic animal model (SNO 2024) - "Anti-androgens enzalutamide and seviteronel prevented DHT-induced nuclear translocation of AR; however, seviteronel did so to a lesser extent, as measured by immunofluorescence and immunoblot...Combining seviteronel with temozolomide limited tumor growth as measured by bioluminescence imaging, but did not significantly extend survival compared to temozolomide alone (n=16, 63.5 vs 56.5 days, p=0.37)... Targeting AR signaling with blood-brain-barrier penetrant anti-androgens may represent a promising biomarker-directed therapeutic strategy. The mechanisms underlying the effects of seviteronel are being further investigated through affinity-purification mass spectrometry analysis and CUT&RUN sequencing of untreated and treated glioma cells. Additional animal experiments are underway to examine the role of biological sex and the glioma immune microenvironment on the efficacy of anti-androgens in vivo."

Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Malignant Glioma • Oncology • Solid Tumor

4CAST: A phase 1b dose exploration, open-label, single-center study evaluating the safety of INO-464 in combination with chemotherapy in patients with metastatic breast cancer. (ASCO 2024) - P1b | "The androgen receptor (AR) antagonist, INO-464, but not abiraterone or enzalutamide, blocks chemotherapy induced cell plasticity to inhibit and primary and metastatic breast cancer (MBC) growth... The MTD of INO-464 is 450mg daily with 0. 5mg dexamethasone in combination with docetaxel or nab-paclitaxel chemotherapy. The combination is well tolerated with early efficacy signals."

Clinical • Combination therapy • Metastases • P1 data • Breast Cancer • Fatigue • Oncology • Pain • Pneumonia • Solid Tumor • Triple Negative Breast Cancer • AR

Targeting androgen receptor signaling in glioblastoma: A novel biomarker and therapeutic approach. (ASCO 2024) - "Glioblastoma cell lines and patient-derived models maintained under stem cell conditions were tested in vitro for their response to anti-androgen therapies (abiraterone, enzalutamide and seviteronel)...Adding seviteronel to temozolomide limited tumor growth by IVIS but did not significantly improve overall survival compared to temozolomide alone (63... Targeting AR with brain penetrant anti-androgen drugs may be a promising biomarker-directed therapeutic strategy for glioblastoma. To address the limitations of our study, further experiments to optimize translational treatment protocols, address the role of biological sex and examine the role of the immune microenvironment are underway."

Biomarker • Brain Cancer • Breast Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • ZEB1

Targeting androgen signaling in glioblastoma (SNO 2023) - "Cytoplasmic AR+ and AR- glioblastoma patient-derived xenografts maintained under stem cell conditions were tested in vitro for their response to anti-androgen therapies (abiraterone, enzalutamide and seviteronel). Glioblastoma is a devastating disease, lacking effective or targeted treatments. Targeting AR with repurposed anti-androgen drugs may be a promising therapeutic strategy, with the potential to abrogate treatment resistance. We are now evaluating these anti-androgen regimens in animal experiments, which will provide a more replicative microenvironment and confirm blood-brain barrier penetrance."

Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • ZEB1

4CAST: Seviteronel in Combination With Chemotherapy in Androgen-receptor Positive Metastatic Triple-negative Breast Cancer (clinicaltrials.gov) - P1b | N=65 | Recruiting | Sponsor: St Vincent's Hospital, Sydney | Not yet recruiting ➔ Recruiting | Trial primary completion date: Jul 2023 ➔ Jul 2024

Combination therapy • Enrollment open • Metastases • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • HER-2 • PGR

Targeting androgen receptor in glioblastoma. (PubMed, Crit Rev Oncol Hematol) - "The first finding in line with expectations is that androgen receptor antagonists, represented by enzalutamide, have been studied and shown to have anti-glioblastoma effects. Expectantly, one of these small molecules, seviteronel, progressed to the Phase II clinical trial stage. These findings suggest that targeting the androgen receptor for glioblastoma may be a promising therapeutic option."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • EGFR

Preclinical and clinical analyses of estrogen receptor alpha mutant metastatic breast cancer (SABCS 2019) - P2; "Colony formation assays and tumor growth were evaluated in the context of treatments targeting ER (fulvestrant), androgen receptors (AR) (enzalutamide), steroid hormone synthesis (CYP17 lyase inhibitor seviteronel), or BRD4 Bromo- and Extra-terminal Domain (BET) inhibitor (BETi: JQ1). AR is induced by stress encountered during disease progression and treatment, such as anchorage independence and estrogen deprivation. Targeting AR may improve the efficacy of agents such as fulvestrant that inhibit ERmut metastatic disease or delay recurrence, as may agents such as BETi that affect the activity of both ER and AR."

AR • CHI3L1 • ER • PGR

Men with advanced breast cancer (BC): Initial phase (Ph) 2 clinical activity of seviteronel, a selective CYP17-lyase and androgen receptor (AR) inhibitor (SABCS 2017) - P1/2; "Seviteronel is active in male BC and was well tolerated with no discontinuations due to AEs. Stage 1 criteria for Sevi activity was met and full Ph 2 enrollment is ongoing for men with BC. In comparison to women with ER+ BC treated with Sevi in Ph 2 (Gucalp et al, ASCO 2017), men had more advanced disease (e.g., visceral disease and prior treatments for metastatic disease)."

Clinical • HER2 Breast Cancer • Hormone Receptor Breast Cancer

4CAST: A Phase 1b dose exploration and dose expansion, open-label study evaluating the safety and efficacy of INO-464 in combination with Chemotherapy in patients with metASTatic breast cancer (SABCS 2022) - P1b | "The antibody-drug conjugate sacituzumab govitecan was been granted recent approval...The androgen receptor (AR) antagonist, INO-464, but not abiraterone or enzalutamide, blocks chemotherapy induced cell plasticity to inhibit and primary and metastatic tumour growth... This investigator-initiated trial is an example of a collaborative effort between the Garvan Institute of Medical Research and the Kinghorn Cancer Centre at St Vincent’s Hospital. If the combination of INO-464 and docetaxel is shown to be safe we look forward to recruiting to the part 2 dose expansion phase across multiple Australian sites."

Clinical • Combination therapy • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • HER-2

Targeting androgen signaling alongside standard care in glioblastoma (LCC 2023) - "Design: Cytoplasmic AR positive and AR negative patient-derived GBM cell lines will be tested for their response to anti-androgen therapies (abiraterone, enzalutamide and seviteronel) alone and in combination with temozolomide chemotherapy. Glioblastoma is a devastating disease, lacking effective or targeted treatments. Targeting AR to eradicate aggressive glioma stem cell populations is a promising therapeutic strategy to improve the efficacy of standard treatments, with the potential to greatly improve outcomes for GBM."

Brain Cancer • Breast Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

State-gating cancer: a new therapeutic strategy to prevent and treat chemotherapy-resistant disease (LCC 2023) - "A clinical trial is now underway testing the anti-androgen agent seviteronel combined with chemotherapy to treat metastatic triple- negative breast cancer. State-gating therapies have transformative clinical potential across multiple cancer types."

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

Phase (Ph) 2 stage 1 clinical activity of seviteronel, a selective CYP17-lyase and androgen receptor (AR) inhibitor, in women with advanced AR+ triple-negative breast cancer (TNBC) or estrogen receptor (ER)+ BC: CLARITY-01. (ASCO 2017) - P1/2; "Sevi Stage 1 activity is suggested by CBRs, along with associated CTC declines in heavily pre-treated pts with high disease burden. The observed safety profile is consistent with on-target pharmacology. Stage 2 enrollment is ongoing."

Clinical • Biosimilar • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Prostate Cancer • Triple Negative Breast Cancer

A phase 2 open-label study to evaluate the efficacy and safety of VT-464 in patients with androgen receptor positive triple-negative breast cancer patients, and men with ER positive breast cancer (AACR 2017) - P2; "...In phase 2 trials androgen blockade with bicalutamide demonstrated a clinical benefit rate (CBR = Partial Response + Complete Response + Stable Disease) of 19% at 24 weeks and enzalutamide showed a CBR of 35% at 16 weeks...Studies in breast cancer cell lines have shown that VT-464 inhibits growth in a soft agar assay of MCF7 (ER positive/low AR expression), tamoxifen-resistant MCF7, and MDA-MB-453 (ER negative/AR positive) cells in a dose dependent manner and with higher potency than enzalutamide...This trial opened in December 2016. While no patients have been enrolled at this time, multiple patients are currently being screened."

P2 data • P2/3 data • P3 data • Biosimilar • Breast Cancer • Gene Therapies • Hepatitis C • Hormone Receptor Breast Cancer • Immunology • Oncology • Triple Negative Breast Cancer

Androgen and oestrogen receptor co-expression determines the efficacy of hormone receptor-mediated radiosensitisation in breast cancer. (PubMed, Br J Cancer) - "While radiosensitising in AR + TNBC, AR inhibition does not modulate radiation sensitivity in AR+/ER+ breast cancer. The efficacy of ER antagonists in combination with RT may also be dependent on AR expression."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • ER

The anti-androgen seviteronel sensitizes triple-negative breast cancer to chemotherapy (AACR 2022) - "Additionally, Phase II clinical trial data demonstrates that seviteronel treatment­ followed by chemotherapy improved survival outcomes in triple-negative breast cancer patients expressing high cytoplasmic AR levels. Seviteronel combined with ­­­­chemotherapy represents a promising therapeutic strategy for triple-negative breast cancer patients."

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

The AR antagonist seviteronel sensitises triple-negative breast cancer to chemotherapy by targeting cancer stem cells (LCC 2022) - P1b | "Together, our work has shed light on the mechanisms that drive cancer stem cell biology, identifying a novel biomarker and therapeutic strategy with the potential to change clinical practice and improve TNBC patient’s outcomes. A clinical trial derived from this work has begun in Australia (NCT04947189)."

Cancer stem cells • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Morusflavone, a New Therapeutic Candidate for Prostate Cancer by CYP17A1 Inhibition: Exhibited by Molecular Docking and Dynamics Simulation. (PubMed, Plants (Basel)) - "Since there are only limited therapeutic agents available, such as abiraterone, galeterone, and seviteronel, which are being developed for prostate cancer, information on any potent natural anticancer compounds, such as vinca alkaloids, for prostate cancer treatment is limited. The results of this study show that CYP17A1 inhibition by Morusflavone could be an important therapeutic target for prostate cancer. Further preclinical and clinical evaluations of the lead compound Morusflavone are required to evaluate whether it can serve as a potential inhibitor of CYP17A1, which will be a new hope for prostate cancer treatment."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CYP17A1

4CAST: Seviteronel in Combination With Chemotherapy in Androgen-receptor Positive Metastatic Triple-negative Breast Cancer (clinicaltrials.gov) - P1b; N=65; Not yet recruiting; Sponsor: St Vincent's Hospital, Sydney; Initiation date: Jul 2021 ➔ Nov 2021

Trial initiation date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • HER-2 • PGR

Stepwise binding of inhibitors to human cytochrome P450 17A1 and rapid kinetics of inhibition of androgen biosynthesis. (PubMed, J Biol Chem) - "Cytochrome P450 (P450) 17A1 catalyzes the 17α-hydroxylation of progesterone and pregnenolone as well as the subsequent lyase cleavage of both products to generate androgens...Here we considered the mechanisms of inhibition of drugs that have been developed to inhibit P450 17A1, including ketoconazole, seviteronel, orteronel, and abiraterone, the only approved inhibitor used for prostate cancer therapy, as well as clotrimazole, known to inhibit P450 17A1...These results are in contrast to inhibitors of P450 3A4, an enzyme with a larger active site in which complete inhibition is not observed with ketoconazole and clotrimazole until the changes are completed. Overall, our the results indicate that both P450 17A1 reactions-17α-hydroxylation and lyase activity-are inhibited by the initial binding of any of these inhibitors, even though subsequent conformational changes occur."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CYP17A1

4CAST: Seviteronel in Combination With Chemotherapy in Androgen-receptor Positive Metastatic Triple-negative Breast Cancer (clinicaltrials.gov) - P1b; N=65; Not yet recruiting; Sponsor: St Vincent's Hospital, Sydney

Clinical • Combination therapy • New P1 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • HER-2 • PGR

Activity of combined androgen receptor antagonism and cell cycle inhibition in androgen receptor-positive triple-negative breast cancer. (PubMed, Mol Cancer Ther) - "The purpose of this study was to investigate the pre-clinical activity of the CDK4/6 inhibitor abemaciclib in combination with an agent that targets both androgen biosynthesis and AR activity, seviteronel, using TNBC cell lines expressing high AR, cell line xenografts and an AR positive, androgen-responsive TNBC patient-derived xenograft (PDX). Implications. While cell cycle inhibitors are FDA-approved for use in ER-positive breast cancer, our studies suggest that they may also be effective in AR+ TNBC, perhaps combined with AR targeted agents."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • ER • HER-2 • PGR