ARV-766 +/- Abiraterone for Prostate Cancer

Not currently recruiting at 26 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Novartis Pharmaceuticals

Must be taking: Androgen deprivation therapy

Must not be taking: Steroids, investigational drugs

Disqualifiers: Brain metastases, gastrointestinal disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new treatment called ARV-766 (Luxdegalutamide), either alone or with abiraterone, to assess its safety and effectiveness for men with metastatic prostate cancer. The trial will include different groups to determine the best approach. Men with metastatic prostate cancer who are already on hormone therapy or have undergone surgery to lower testosterone might be suitable candidates. As a Phase 1 and Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group. Participants have the opportunity to contribute to groundbreaking advancements in prostate cancer treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking any systemic anti-cancer therapy at least 2 weeks before starting the study drug, except for medications that maintain castrate status. If you are taking bicalutamide, mitomycin C, or nitrosoureas, you need to stop 6 weeks before, and if you are taking abiraterone, you need to stop 4 weeks before.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ARV-766 holds promise for treating prostate cancer. In one study, many patients experienced a significant drop in PSA levels, a protein linked to prostate cancer. Importantly, no serious side effects emerged that required stopping treatment, suggesting it is well-tolerated.

The safety of combining ARV-766 with abiraterone is still under investigation. However, abiraterone is already approved for treating prostate cancer, indicating its safety for this purpose. Overall, current data suggests that ARV-766 and its combination with abiraterone appear to be safe options. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ARV-766 because it offers a novel approach to treating prostate cancer by degrading androgen receptor proteins, which are essential for cancer cell growth. Unlike standard treatments like hormone therapies or chemotherapy that aim to block or reduce hormone production, ARV-766 directly targets and breaks down the proteins that drive cancer growth. This unique mechanism of action could potentially overcome resistance to existing treatments and offer new hope for patients with advanced prostate cancer. When combined with Abiraterone, another oral medication that inhibits hormone production, ARV-766 could enhance treatment effectiveness, providing a powerful one-two punch against the disease.

What evidence suggests that this trial's treatments could be effective for prostate cancer?

Research has shown that ARV-766, a drug that helps break down proteins linked to prostate cancer, delivers promising results. In earlier studies, 42% of patients experienced a drop in their Prostate-Specific Antigen (PSA) levels by more than half. PSA serves as a marker for tracking prostate cancer. ARV-766 was well-tolerated, meaning it did not cause serious side effects. In this trial, some participants will receive ARV-766 alone, while others will receive a combination of ARV-766 and abiraterone. The combination might enhance results further, as ARV-766 and abiraterone together could more effectively slow cancer growth. ^{1 2 3 6 7}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

Men with metastatic prostate cancer who've had progression after at least two systemic therapies, including a second-generation androgen inhibitor. They must have an ECOG performance status of 0 or 1, be on ADT, and can't have had more than two chemo regimens. Exclusions include recent anti-cancer therapy, certain gastrointestinal conditions, symptomatic brain metastases requiring steroids, recent radiation therapy or investigational drugs.

Inclusion Criteria

I am currently on hormone therapy for cancer or have had an orchiectomy.

My prostate cancer has worsened despite two prior treatments, including a modern hormone therapy.

I have taken 1-3 types of specific prostate cancer drugs and no more than 2 chemotherapy treatments for my advanced prostate cancer.

Exclusion Criteria

I have previously been treated with a second generation NHA.

Part A and B: Known symptomatic brain metastases requiring steroids (above physiologic replacement doses). Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease, or previous gastric resection or lap band surgery. Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to >25% of the bone marrow. Receipt of an investigational drug(s) within 4 weeks prior to anticipated first dose. Systemic anti-cancer therapy within 2 weeks of first dose of study drug (except agents to maintain castrate status). For bicalutamide, mitomycin C, or nitrosoureas the exclusion period must be 6 weeks and for abiraterone 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ARV-766 monotherapy or in combination with abiraterone in 28-day cycles

12 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• ARV-766

Trial Overview The trial is testing ARV-766 alone (Part A&B) and in combination with abiraterone (Part C&D), taken orally for men with advanced prostate cancer. It's to see how safe they are and how well they work as treatments.

How Is the Trial Designed?

Group I: ARV-766 + Abiraterone Experimental Treatment 1 Intervention

Oral tablets, once daily in 28 day cycles

Group II: ARV-766 Experimental Treatment 1 Intervention

Oral tablets, once daily in 28 day cycles

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Arvinas Androgen Receptor, Inc.

Lead Sponsor

Trials

4

Recruited

450+

Published Research Related to This Trial

In a phase 3 trial involving 1199 patients, the addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly improved overall survival, with a median survival not reached in the abiraterone group compared to 34.7 months in the placebo group.

The study also showed that patients receiving abiraterone had a median radiographic progression-free survival of 33.0 months, compared to 14.8 months in the placebo group, indicating a strong benefit in delaying disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. Fizazi, K., Tran, N., Fein, L., et al.[2022]

In a study of 68 patients with metastatic prostate cancer treated with abiraterone acetate, higher plasma trough concentrations of abiraterone (≥ 20.6 ng/mL) were significantly linked to an increased risk of adverse events (AEs) and treatment withdrawal.

Monitoring abiraterone plasma levels may be beneficial for managing treatment in prostate cancer patients, as high concentrations were identified as independent risk factors for both AEs and the time to discontinue therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate. Takahashi, Y., Narita, S., Shiota, M., et al.[2023]

A novel RNA in situ hybridization (RISH) assay was developed to specifically detect and quantify androgen receptor splice variant 7 (AR-V7) in prostate cancer biopsies, showing a positive detection rate of 34.1% in metastatic castration-resistant prostate cancer (mCRPC) specimens.

Higher levels of AR-V7 detected using this method were significantly associated with shorter progression-free survival in patients treated with abiraterone or enzalutamide, indicating that AR-V7 may serve as a biomarker for treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Zhu, Y., Sharp, A., Anderson, CM., et al.[2023]

In a study of 12 men with metastatic castrate-resistant prostate cancer (mCRPC) who were re-treated with abiraterone acetate (AA), only 46% of those who initially responded to AA showed a similar response upon re-treatment, indicating limited efficacy.

The median duration of response to AA re-treatment was short, with a median biochemical progression-free survival of just 2.3 months, suggesting that re-challenging with AA may not provide significant long-term benefits for most patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone. Leibowitz-Amit, R., Alimohamed, N., Vera-Badillo, FE., et al.[2016]

In a study of 159 metastatic castration-resistant prostate cancer (mCRPC) patients, early-onset therapy with abiraterone acetate plus prednisone (AA + P) showed a median overall survival of 22.3 months, while late-onset therapy had a median overall survival of 39.2 months, indicating that timing of treatment may impact survival outcomes.

The treatment was generally well tolerated, with low incidence of serious adverse events (SAEs) reported, suggesting that AA + P is a safe option for mCRPC patients in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Early- vs. late-onset treatment using abiraterone acetate plus prednisone in chemo-naïve, asymptomatic or mildly symptomatic patients with metastatic CRPC after androgen deprivation therapy]. Merseburger, AS., Rüssel, C., Belz, H., et al.[2022]

Abiraterone is an oral medication that inhibits a key enzyme involved in androgen production, making it effective for treating metastatic castration-resistant prostate cancer.

The drug is FDA approved for use in men with this type of cancer, both before and after chemotherapy, and can be administered even to patients on hemodialysis, highlighting its versatility in challenging clinical situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone experience in a patient with metastatic castration-resistant prostate cancer on hemodialysis. Karakurt Eryılmaz, M., Karaağaç, M.[2020]

In a study involving 1919 patients with metastatic prostate cancer, the addition of abiraterone acetate to standard androgen deprivation therapy significantly improved overall survival, with a median survival of 76.6 months compared to 45.7 months for standard care alone.

Combining both abiraterone and enzalutamide did not provide additional survival benefits over abiraterone alone, and it was associated with higher rates of severe side effects, suggesting that this combination should be avoided in long-term treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol. Attard, G., Murphy, L., Clarke, NW., et al.[2023]

In a study involving 1,311 men with metastatic castration-resistant prostate cancer, the addition of abiraterone acetate and prednisone to enzalutamide did not significantly improve overall survival compared to enzalutamide alone, with median survival times of 32.7 months versus 34.2 months, respectively.

However, the combination treatment did result in longer radiographic progression-free survival (24.3 months vs. 21.3 months), indicating some benefit in delaying disease progression, although increased clearance of abiraterone when combined with enzalutamide may have influenced these outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial). Morris, MJ., Heller, G., Hillman, DW., et al.[2023]

A new non-invasive assay was developed to monitor androgen receptor (AR) expression in circulating tumor cells (CTCs) from 48 metastatic castration-resistant prostate cancer (CRPC) patients, revealing significant variability in AR expression among patients.

The study found that prior treatment with abiraterone or enzalutamide did not change AR expression levels in CTCs, and maintained nuclear AR expression was confirmed in tissue samples from patients who progressed on these treatments, indicating potential resistance mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Androgen receptor expression in circulating tumour cells from castration-resistant prostate cancer patients treated with novel endocrine agents. Crespo, M., van Dalum, G., Ferraldeschi, R., et al.[2022]

In a study of 3808 men with metastatic castration-resistant prostate cancer (mCRPC), African American men receiving first-line abiraterone therapy had a significantly higher median overall survival (23 months) compared to non-Hispanic White men (17 months).

The study found no overall survival difference between first-line abiraterone and enzalutamide for African American men, while non-Hispanic White men had decreased survival with abiraterone compared to enzalutamide, suggesting that race may influence treatment outcomes in mCRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes Among African American and Non-Hispanic White Men With Metastatic Castration-Resistant Prostate Cancer With First-Line Abiraterone. Marar, M., Long, Q., Mamtani, R., et al.[2022]

In a study involving 1917 men with locally advanced or metastatic prostate cancer, the combination of abiraterone acetate and prednisolone with androgen-deprivation therapy (ADT) significantly improved overall survival compared to ADT alone, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

The combination therapy also resulted in a much lower rate of treatment failure, with a hazard ratio of 0.29, meaning patients were less likely to experience disease progression compared to those receiving only ADT, although it was associated with a higher incidence of grade 3 to 5 adverse events (47% vs. 33%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. James, ND., de Bono, JS., Spears, MR., et al.[2023]

In a review of seven randomized controlled trials involving 7103 patients with castration-resistant prostate cancer, abiraterone was found to significantly increase the risk of both any grade (RR = 1.34) and severe grade (RR = 1.71) cardiac disorders.

Enzalutamide was associated with a much higher risk of developing any grade (RR = 2.66) and severe grade (RR = 2.79) hypertension, indicating that while both drugs have cardiovascular risks, they affect different aspects of heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone and enzalutamide had different adverse effects on the cardiovascular system: a systematic review with pairwise and network meta-analyses. Lee, HY., Chen, HL., Teoh, JY., et al.[2022]

A meta-analysis of 7 studies involving 8660 patients found that the use of new hormonal agents like abiraterone and enzalutamide significantly increases the risk of cardiovascular toxicity, with relative risks of 1.36 for all-grade and 1.84 for high-grade cardiac toxicity.

Abiraterone specifically raises the risk of both cardiac toxicity and hypertension, while enzalutamide primarily increases the risk of hypertension, highlighting the need for careful monitoring of cardiovascular health in patients undergoing treatment for metastatic prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer. Iacovelli, R., Ciccarese, C., Bria, E., et al.[2021]

In a study involving 2267 patients with metastatic castration-resistant prostate cancer, long-term use of low-dose prednisone (5mg twice daily) with or without abiraterone acetate resulted in a low incidence of corticosteroid-associated adverse events (CA-AEs), with only 25% of patients experiencing any grade CA-AEs.

The most common CA-AEs were hyperglycemia and weight increase, but the overall frequency of these events did not increase with longer exposure to prednisone, indicating that the treatment is safe and tolerable over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Incidence of Corticosteroid-associated Adverse Events on Long-term Exposure to Low-dose Prednisone Given with Abiraterone Acetate to Patients with Metastatic Castration-resistant Prostate Cancer. Fizazi, K., Chi, KN., de Bono, JS., et al.[2022]

In a study of 137 chemo-naïve patients with metastatic castration-resistant prostate cancer, Enzalutamide (EZ) showed a significantly higher PSA response rate compared to Abiraterone (AA) in the first line of treatment (95.9% vs 67%).

Both AA and EZ had comparable toxicity rates and progression-free survival (PFS) outcomes, indicating that both treatments are effective and well-tolerated options for managing mCRPC without chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing lines of therapy in castration-resistant prostate cancer: real-life snapshot from a multicenter cohort. Ferriero, M., Mastroianni, R., De Nunzio, C., et al.[2021]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.5011

ARV-766, a proteolysis targeting chimera (PROTAC) ... ARV-766 is a novel, potent, orally administered PROTAC AR degrader that targets wild-type AR and clinically relevant AR LBD mutants.

2. urotoday.com urotoday.com/video-lectures/mcrpc-treatment/video/4110-arv-766-efficacy-and-safety-of-a-second-generation-ar-degrader-in-prostate-cancer-daniel-petrylak.html

ARV-766: Efficacy and Safety of a Second-Generation AR ... The study shows promising results, with significant PSA reductions and manageable side effects. Dr. Petrylak envisions future trials ...

3. onclive.com onclive.com/view/arv-766-demonstrates-clinical-activity-in-ar-lbd-mutated-metastatic-crpc

ARV-766 Demonstrates Clinical Activity in AR LBD ... ARV-766 demonstrated a 43% PSA decline of at least 50% in patients with AR LBD mutations. · No dose-limiting toxicities were observed, and the ...

4. 2minutemedicine.com 2minutemedicine.com/novartis-arv-766-is-an-androgen-receptor-degrader-efficacious-in-treating-metastatic-prostate-cancer/

Novartis: ARV-766 is an androgen receptor degrader ... Preliminary data from the study showed that ARV-766 led to a greater than 50% reduction in Prostate-Specific antigen (PSA) in 42% of patients ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05067140

NCT05067140 | A Study of ARV-766 Given by Mouth in ... A Phase 1/2 study to evaluate the safety and efficacy of ARV-766 given by mouth alone or in combination with abiraterone in men with metastatic prostate cancer.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10854644/

Insight into Recent Advances in Degrading Androgen ... As of now, only ARV-110 and ARV-766 have advanced to phase II clinical trials as AR PROTACs. Additionally, four other AR PROTACs (three for ...

7. ir.arvinas.com ir.arvinas.com/news-releases/news-release-details/arvinas-announces-interim-data-arv-766-phase-12-dose-escalation

Arvinas Announces Interim Data from the ARV-766 Phase ... Data from the Phase 1/2 dose escalation and expansion trial show that ARV-766 was well-tolerated and demonstrated promising activity in a heavily pre-treated, ...