Enzalutamide + ADT for Metastatic Prostate Cancer

(ENZAMET Trial)

Recruiting at 84 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 3

Sponsor: University of Sydney

Must be taking: LHRHA, NSAA

Disqualifiers: Seizure history, Cardiovascular disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 3 years

1125 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of a drug called enzalutamide when combined with standard treatments for newly diagnosed metastatic prostate cancer. It compares enzalutamide to a common non-steroidal anti-androgen, a type of hormone therapy, to determine which is more effective. Men about to begin hormone therapy for prostate cancer that has spread to other parts of the body are suitable candidates for this trial. As a Phase 3 trial, this research represents the final step before FDA approval, giving participants the opportunity to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on anti-retroviral drugs for HIV, they must be unaffected by enzalutamide. It's best to discuss your specific medications with the trial team.

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

Research has shown that enzalutamide is generally well-tolerated for treating advanced prostate cancer. A large study found that enzalutamide lowered the risk of death by 33% compared to those not taking it, indicating its effectiveness and relative safety. Another study reported that 80% of patients taking enzalutamide were alive after three years, compared to 72% receiving standard care.

While enzalutamide appears promising, awareness of possible side effects, such as tiredness, high blood pressure, and hot flashes, is important. These side effects are often manageable. Overall, the benefits of enzalutamide seem to outweigh the risks for many patients.

The FDA has approved enzalutamide for other prostate cancer treatments, supporting its safety. Consulting a healthcare provider can help determine if joining a trial is the right choice. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for prostate cancer?

Researchers are excited about enzalutamide for metastatic prostate cancer because it offers a novel approach by blocking androgen receptors more effectively than conventional non-steroidal anti-androgens (NSAAs). While standard treatments often include LHRH analogs or surgical castration to reduce androgen production, enzalutamide goes a step further by preventing androgens from activating prostate cancer cells, potentially leading to better disease control. Additionally, enzalutamide is conveniently taken as a daily oral pill, which could improve patient adherence compared to more invasive therapies.

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

Studies have shown that enzalutamide, one of the treatments in this trial, can be very effective for treating metastatic prostate cancer when combined with standard treatments like hormone therapy. Research indicates that enzalutamide can help patients live longer, with 50% of patients surviving at 96 months, compared to 40% with conventional treatments. It also lowers the risk of death by 33% compared to other therapies and significantly extends the time patients live without their cancer worsening. These findings suggest enzalutamide is a promising option for those newly diagnosed with metastatic prostate cancer. Another treatment arm in this trial involves the use of conventional NSAA, which will be compared to enzalutamide to evaluate effectiveness. ^{2 3 4 5 6}

Who Is on the Research Team?

Christopher Sweeney

Principal Investigator

Dana Farber Cancer Institute and ANZUP

Ian Davis

Principal Investigator

ANZUP and Eastern Health Box Hill Hospital

Are You a Good Fit for This Trial?

Men 18+ with newly diagnosed metastatic prostate cancer can join this trial. They must have certain levels of blood cells, liver and kidney function, and be able to start treatment within a week after joining. Those with specific heart conditions, other cancers in the past 5 years, or severe infections cannot participate.

Inclusion Criteria

Presence of target or non-target lesions according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1

Willing and able to comply with all study requirements, including treatment and required assessments

Has completed baseline Health-Related Quality of Life (HRQL) questionnaires unless unable due to limited literacy or vision

Exclusion Criteria

Life expectancy of less than 12 months

Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases

My prostate cancer has specific aggressive features.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive enzalutamide or conventional NSAA with LHRHA or surgical castration until clinical disease progression or prohibitive toxicity

Up to 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Enzalutamide
• LHRHA or Surgical Castration
• NSAA

Trial Overview The study is testing if enzalutamide is more effective than traditional anti-androgens when combined with hormone therapy or surgery for first line treatment of advanced prostate cancer. Participants will receive either enzalutamide or a non-steroidal anti-androgen as part of their therapy.

How Is the Trial Designed?

Group I: Enzalutamide Experimental Treatment 2 Interventions

Enzalutamide is 160 mg daily, by mouth, until clinical disease progression or prohibitive toxicity. All participants are to receive standard background therapy with a LHRHA or surgical castration, as per standard of care. The choice of the LHRHA or surgical castration is at the discretion of the treating clinician.

Group II: Conventional NSAA Active Control 2 Interventions

Conventional NSAA, by mouth until clinical disease progression or prohibitive toxicity. All participants are to receive standard background therapy with a LHRHA or surgical castration, as per standard of care. The choice of the LHRHA or surgical castration is at the discretion of the treating clinician.

Enzalutamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in European Union as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in Canada as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in Japan as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Who Is Running the Clinical Trial?

University of Sydney

Lead Sponsor

Trials

208

Recruited

417,000+

Astellas Pharma Inc

Industry Sponsor

Trials

700

Recruited

236,000+

Headquarters

Tokyo, Japan

Top Products

- Xtandi (enzalutamide) for prostate cancer, - Xospata (gilteritinib) for AML, - Padcev (enfortumab vedotin) for bladder cancer, - Prograf (tacrolimus) for organ rejection prevention

Tadaaki Taniguchi

Astellas Pharma Inc

Chief Medical Officer since 2023

MD, PhD

Naoki Okamura

Astellas Pharma Inc

Chief Executive Officer since 2023

University of Tokyo, Faculty of Pharmacy

NCIC Clinical Trials Group

Collaborator

Trials

190

Recruited

145,000+

National Health and Medical Research Council, Australia

Collaborator

Trials

167

Recruited

473,000+

Canadian Cancer Trials Group

Collaborator

Trials

135

Recruited

70,300+

Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Collaborator

Trials

21

Recruited

7,000+

Cancer Trials Ireland

Collaborator

Trials

85

Recruited

25,600+

Published Research Related to This Trial

Enzalutamide, a treatment for metastatic castration-resistant prostate cancer, was linked to a case of acute generalized exanthematous pustulosis (AGEP) in a 62-year-old male patient, indicating a potential skin-related side effect of this medication.

The patient's skin reaction occurred shortly after starting enzalutamide and resolved within four weeks, suggesting that the long half-life of enzalutamide (5.8 days) may contribute to the prolonged duration of symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide induced acute generalized exanthematous pustulosis. Alberto, C., Konstantinou, MP., Martinage, C., et al.[2020]

Castration remains a primary treatment for advanced prostate cancer, achieving an initial response rate of over 60-70%, but the effectiveness typically lasts less than 3 to 5 years due to resistance mechanisms like increased adrenal androgens or mutated androgen receptors.

Newer treatments like abiraterone and enzalutamide show promise as effective second-line therapies for castration-resistant prostate cancer and may also be beneficial as initial treatments, but their use as standard care requires validation through randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line use of novel hormonal agents in prostate cancer: a critical appraisal. Raghavan, D.[2018]

In a phase III trial involving 1,150 men with metastatic hormone-sensitive prostate cancer, enzalutamide combined with androgen deprivation therapy significantly reduced the risk of radiographic progression or death compared to placebo, with a hazard ratio of 0.39, indicating a strong efficacy.

The safety profile of enzalutamide was consistent with previous studies, showing similar rates of grade 3 or greater adverse events between the enzalutamide and placebo groups (24.3% vs. 25.6%), suggesting it is a safe treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. Armstrong, AJ., Szmulewitz, RZ., Petrylak, DP., et al.[2021]

In the PREVAIL study involving 872 men with metastatic castration-resistant prostate cancer, significant declines in prostate-specific antigen (PSA) levels after 3 months of enzalutamide treatment were linked to improved overall survival and progression-free survival outcomes.

Specifically, 88% of patients experienced a PSA decline of at least 30%, and greater declines were associated with longer survival and better quality of life, indicating that monitoring PSA levels can provide valuable prognostic information for treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic Association of Prostate-specific Antigen Decline with Clinical Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide in a Randomized Clinical Trial. Armstrong, AJ., Lin, P., Higano, CS., et al.[2021]

In a phase 3 trial involving 1401 men with nonmetastatic, castration-resistant prostate cancer, enzalutamide significantly improved median overall survival to 67.0 months compared to 56.3 months for placebo, indicating a 27% lower risk of death.

The safety profile of enzalutamide was consistent with previous studies, with a similar rate of serious adverse events compared to placebo, primarily involving fatigue and musculoskeletal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. Sternberg, CN., Fizazi, K., Saad, F., et al.[2021]

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]

Enzalutamide (XTANDI) is an FDA-approved treatment for castration-resistant prostate cancer (CRPC) that effectively targets androgen receptor signaling, which is crucial for cancer progression.

In a Phase III clinical trial involving men with CRPC after chemotherapy, enzalutamide was well tolerated and significantly improved overall survival by 4.8 months, as indicated by reduced serum prostate-specific antigen (PSA) levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel anti-androgen with prolonged survival rate in CRPC patients. Dhingra, R., Sharma, T., Singh, S., et al.[2021]

Enzalutamide is an effective androgen receptor inhibitor that improves overall survival in patients with metastatic castration-resistant prostate cancer, showing a 4.8-month survival benefit in those previously treated with docetaxel, as demonstrated in the Phase III AFFIRM trial.

The FDA has expanded enzalutamide's approval to include first-line treatment for metastatic castration-resistant prostate cancer in patients who have not yet received chemotherapy, and it is associated with an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide for patients with metastatic castration-resistant prostate cancer. Ramadan, WH., Kabbara, WK., Al Basiouni Al Masri, HS.[2020]

Enzalutamide combined with androgen deprivation therapy (ADT) significantly reduces the risk of death in men with non-metastatic castration-resistant prostate cancer (nmCRPC), regardless of age or region, based on a study involving 1401 participants with a median age of 74 years.

The safety profile of enzalutamide was consistent across different age groups and regions, with treatment-emergent adverse events being more common in the placebo group, indicating that enzalutamide is a safe option for older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consistent survival benefit of enzalutamide plus androgen deprivation therapy in men with nonmetastatic castration-resistant prostate cancer: PROSPER subgroup analysis by age and region. De Giorgi, U., Hussain, M., Shore, N., et al.[2022]

In the ARCHES study involving 1150 patients with metastatic hormone-sensitive prostate cancer, the addition of enzalutamide to androgen deprivation therapy (ADT) significantly delayed the worsening of pain and maintained health-related quality of life (HRQoL) compared to placebo.

While there were no significant differences in overall HRQoL scores between the enzalutamide and placebo groups, enzalutamide specifically delayed the time to first deterioration in pain severity and quality of life measures, indicating its potential to improve patient comfort during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Enzalutamide plus Androgen Deprivation Therapy on Health-related Quality of Life in Patients with Metastatic Hormone-sensitive Prostate Cancer: An Analysis of the ARCHES Randomised, Placebo-controlled, Phase 3 Study. Stenzl, A., Dunshee, C., De Giorgi, U., et al.[2021]

A 76-year-old man developed severe thrombocytopenia after 13 days of enzalutamide treatment for castration-resistant prostate cancer, indicating that this side effect can occur early in therapy.

After discontinuing enzalutamide, the patient's platelet count recovered, and he was able to restart the medication without recurrence of thrombocytopenia; however, he later experienced a seizure, suggesting that enzalutamide may also be associated with neurological adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide-induced severe thrombocytopenia complicated by a seizure in a 76-year-old man with castration-resistant prostate cancer. Murata, M., Takizawa, I., Maruyama, R., et al.[2022]

Citations

1. pfizer.com pfizer.com/news/press-release/press-release-detail/astellas-and-pfizers-xtanditm-enzalutamide-shows-long-term

Astellas and Pfizer's XTANDI™ (enzalutamide) Shows ... OS at 96 months was 50% with XTANDI and 40% for NSAA; progression-free survival (PFS) also favored XTANDI over NSAA (HR: 0.49; 95% CI, 0.42-0.57) ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40660075/

The efficacy and safety of enzalutamide in metastatic ... Results: The data of 2275 patients were analyzed eventually. Enzalutamide reduced the risk of death by 33% compared to the control. Specifically ...

3. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2833622

Enzalutamide and Prostate-Specific Antigen Levels in ... In this study, enzalutamide plus ADT was associated with improved outcomes in men with mHSPC regardless of pretreatment PSA level.

4. xtandihcp.com xtandihcp.com/cspc/efficacy

Efficacy CSPC | HCP Site | XTANDI® (enzalutamide) XTANDI (single agent) significantly improved metastasis-free survival vs placebo + GnRH therapy* · Number of events: 63 (17.7%) with XTANDI (single agent) vs 92 ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1903835

Enzalutamide with Standard First-Line Therapy in ... Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12504157/

Comparative effectiveness and safety of enzalutamide ... Effectiveness outcomes included all-cause death, prostate cancer-related death, and treatment failure. Safety outcomes included major adverse CV ...