Enzalutamide + ADT for Metastatic Prostate Cancer

(ENZAMET Trial)

Recruiting at 83 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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine the effectiveness of enzalutamide, versus a conventional non-steroidal anti androgen (NSAA), when combined with a luteinizing hormone releasing hormone analog (LHRHA) or surgical castration, as first line androgen deprivation therapy (ADT) for newly diagnosed metastatic prostate cancer.

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.

What data supports the effectiveness of the drug Enzalutamide for treating metastatic prostate cancer?

Research shows that Enzalutamide, when combined with androgen deprivation therapy (ADT), improves clinical outcomes in men with metastatic hormone-sensitive prostate cancer. It has also been shown to significantly prolong survival in patients with nonmetastatic, castration-resistant prostate cancer. ^{1 2 3 4 5}

Is the combination of Enzalutamide and ADT safe for treating metastatic prostate cancer?

Enzalutamide, used with androgen deprivation therapy (ADT), has been shown to be generally safe in humans, but it can cause side effects like severe thrombocytopenia (low platelet count) and seizures in some cases. It is well tolerated in many patients, with studies showing it can improve survival in men with castration-resistant prostate cancer. ^{6 7 8 9 10}

How is the drug Enzalutamide + ADT unique for treating metastatic prostate cancer?

Enzalutamide combined with androgen deprivation therapy (ADT) is unique because it significantly improves survival outcomes in patients with metastatic prostate cancer by targeting the androgen receptor pathway more effectively than ADT alone, offering a new approach for those who do not respond well to traditional castration methods. ^{5 6 11 12 13}

Research Team

Christopher Sweeney

Principal Investigator

Dana Farber Cancer Institute and ANZUP

Ian Davis

Principal Investigator

ANZUP and Eastern Health Box Hill Hospital

Eligibility Criteria

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

I am a man over 18 with advanced prostate cancer.

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

My liver functions within the normal range, even if I have liver metastases.

Exclusion Criteria

Life expectancy of less than 12 months

My prostate cancer has specific aggressive features.

I have had hormone therapy for prostate cancer, but only in certain situations.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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, 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]

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]

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]

References

1. Netherlands 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. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer by Pattern of Metastatic Spread: ARCHES Post Hoc Analyses. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. [2021]

5. England 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. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Enzalutamide for patients with metastatic castration-resistant prostate cancer. [2020]

7. Australia pubmed.ncbi.nlm.nih.gov

Enzalutamide-induced severe thrombocytopenia complicated by a seizure in a 76-year-old man with castration-resistant prostate cancer. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Managing lines of therapy in castration-resistant prostate cancer: real-life snapshot from a multicenter cohort. [2021]

9. United States 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. [2021]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel anti-androgen with prolonged survival rate in CRPC patients. [2021]

11. Poland pubmed.ncbi.nlm.nih.gov

Enzalutamide induced acute generalized exanthematous pustulosis. [2020]

12. Switzerland 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. [2021]

13. United States pubmed.ncbi.nlm.nih.gov

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