Enzalutamide + Standard Therapy for Prostate Cancer

(DIRECT Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Age: 18+

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University Health Network, Toronto

Must be taking: Hormone therapy

Disqualifiers: Significant comorbidities, Recent malignancy, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing if adding enzalutamide, a pill that blocks male hormones, to standard radiation and hormone treatments can improve the quality of life for prostate cancer patients. Participants will receive treatments and be monitored over several months and years to see how they do. Enzalutamide is an antiandrogen used to treat both metastatic and nonmetastatic prostate cancer.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug enzalutamide in treating prostate cancer?

Research shows that adding enzalutamide to standard treatment for men with metastatic hormone-sensitive prostate cancer helps them live longer compared to older drugs. Additionally, enzalutamide combined with androgen deprivation therapy (ADT) improves the time patients live without the cancer getting worse. ^{1 2 3 4 5}

Is the combination of Enzalutamide and standard therapy for prostate cancer safe?

Enzalutamide, used in prostate cancer treatment, has been associated with severe thrombocytopenia (low platelet count) and seizures in some cases. Additionally, there are cardiovascular risks linked to androgen deprivation therapy (ADT), which is often part of the treatment. ^{1 3 4 6 7}

How is the treatment with Enzalutamide and Standard Therapy unique for prostate cancer?

This treatment is unique because it combines enzalutamide, a newer androgen receptor-targeting drug, with standard therapies to improve survival in men with metastatic hormone-sensitive prostate cancer, outperforming older nonsteroidal antiandrogen drugs. ^{1 3 8 9 10}

Research Team

Eligibility Criteria

Men over 18 with a specific type of prostate cancer that has spread only slightly (oligometastatic) and who haven't had certain other cancers or treatments in the last 5 years. They should be relatively healthy, able to consent, and not on continuous hormone therapy for their cancer.

Inclusion Criteria

I have been diagnosed with prostate cancer.

Maximum one metastatic deposit on conventional imaging (CT or bone scan or MR)

I choose not to use hormone therapy continuously.

Exclusion Criteria

I have had treatment to control cancer after the first treatment failed.

I haven't had any cancer except for non-melanoma skin cancer or in-situ cancer in the last 5 years.

I have health issues that make me unsuitable for certain prostate cancer treatments.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard of care radiation and hormone (ADT) therapy, with or without oral abiraterone for 8-9 months

8-9 months

2-5 sessions of radiation daily or every other day

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Routine follow-up in clinic or remotely

Treatment Details

Interventions

• ADT (Hormone Therapy)
• Enzalutamide (Antiandrogen)
• Standard of Care SBRT (Procedure)

Trial Overview The trial is testing if adding a drug called Enzalutamide to standard radiation and hormone therapy improves life quality for men with limited-spread prostate cancer. Participants are randomly chosen to receive either just the standard treatment or the standard plus Enzalutamide for eight months.

Participant Groups

Group I: Arm 3 - Study Treatment Experimental Treatment 2 Interventions

Participants in this group will receive standard of care radiation treatment and ADT, plus abiraterone. Participants will start ADT first. Androgen deprivation therapy will be delivered via injection every 4 months as per standard of care (for 8 months total). At the same time, or within 3 months of starting ADT, participants will begin radiation treatment. The radiation treatment course will consist of 2-5 sessions of radiation daily or every other day (the number of sessions will be determined by the physician depending on the location of cancer, number of cancer spots, etc.). In addition, participants will take abiraterone orally (by mouth) daily for 8-9 months. Participants will start the first pill within a month of enrollment. This pill can be taken around the same time of day with or without food.

Group II: Arm 1 - Standard of Care Experimental Treatment 1 Intervention

Participants in this group will receive standard of care radiation treatment and ADT. Participants will start ADT first. Androgen deprivation therapy will be delivered via injection every 4 months as per standard of care (for 8 months total). At the same time, or within 3 months of starting ADT, participants will begin radiation treatment. The radiation treatment course will consist of 2-5 sessions of radiation daily or every other day (the number of sessions will be determined by the physician depending on the location of cancer, number of cancer spots, etc.).

ADT is already approved in Canada, Japan, China, Switzerland for the following indications:

Approved in Canada as Androgen Deprivation Therapy for:

• Prostate Cancer

Approved in Japan as Androgen Deprivation Therapy for:

• Prostate Cancer

Approved in China as Androgen Deprivation Therapy for:

• Prostate Cancer

Approved in Switzerland as Androgen Deprivation Therapy for:

• Prostate Cancer

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Dr. Brad Wouters

University Health Network, Toronto

Chief Medical Officer since 2020

MD from University of Toronto

Dr. Kevin Smith

University Health Network, Toronto

Chief Executive Officer since 2018

Professor at McMaster University and University of Toronto

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

Findings from Research

The ENZAMET phase III trial demonstrated that adding enzalutamide to standard treatment significantly prolongs survival in men with metastatic hormone-sensitive prostate cancer.

Enzalutamide is more effective than older nonsteroidal antiandrogen drugs, highlighting its potential as a superior treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide Bests Older NSAAs in mHSPC. [2021]

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]

In the phase 3 ARCHES trial involving 1150 patients with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide combined with androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival (rPFS) with a hazard ratio of 0.39, indicating a strong reduction in the risk of disease progression.

The efficacy of enzalutamide plus ADT was consistent across various patient subgroups, including those with different prior treatments, disease volumes, and risk levels, demonstrating its broad clinical benefit for mHSPC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of enzalutamide in subgroups of men with metastatic hormone-sensitive prostate cancer based on prior therapy, disease volume, and risk. Azad, AA., Armstrong, AJ., Alcaraz, A., et al.[2022]

In a study involving 1974 men with high-risk non-metastatic prostate cancer, combination therapy with abiraterone acetate and prednisolone significantly improved metastasis-free survival compared to androgen-deprivation therapy (ADT) alone, with a hazard ratio of 0.53, indicating a 47% reduction in the risk of metastasis.

The combination therapy also showed significant improvements in overall survival, prostate cancer-specific survival, and biochemical failure-free survival, although it was associated with a higher incidence of grade 3 or higher adverse events, such as hypertension and liver enzyme elevation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Attard, G., Murphy, L., Clarke, NW., et al.[2023]

In a study of 129 patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide, nearly half (around 49-51%) showed significant declines in PSA levels at various time points, indicating a positive response to the treatment.

The study found that a decline in PSA levels was a significant predictor of improved overall survival, particularly notable at 12 weeks, supporting the use of PSA responses as a valuable prognostic marker in heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PSA declines and survival in patients with metastatic castration-resistant prostate cancer treated with enzalutamide: A retrospective case-report study. Bosso, D., Pagliuca, M., Sonpavde, G., et al.[2022]

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]

Abiraterone therapy is associated with significantly higher odds of cardiac adverse events, including myocardial infarction and heart failure, compared to other medications, indicating a potential cardiovascular risk for patients on this treatment.

In contrast, enzalutamide did not show a similar increase in cardiac risks, suggesting it may be a safer option for patients with existing heart conditions when compared to abiraterone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular toxicities associated with abiraterone compared to enzalutamide-A pharmacovigilance study. Cone, EB., Reese, S., Marchese, M., et al.[2022]

In a study of 38 patients with non-metastatic castration sensitive prostate cancer, three months of enzalutamide treatment led to a remarkable 99% decline in prostate-specific antigen (PSA) levels, demonstrating its efficacy without the need for androgen deprivation therapy (ADT).

Enzalutamide treatment was associated with beneficial immune changes, including an increase in natural killer cells and naïve T cells, suggesting potential for future combination therapies in immunotherapy for prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer. Madan, RA., Karzai, F., Donahue, RN., et al.[2021]

References

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

Enzalutamide Bests Older NSAAs in mHSPC. [2021]

2. 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]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy of enzalutamide in subgroups of men with metastatic hormone-sensitive prostate cancer based on prior therapy, disease volume, and risk. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. [2023]

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

PSA declines and survival in patients with metastatic castration-resistant prostate cancer treated with enzalutamide: A retrospective case-report study. [2022]

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

Cardiovascular toxicities associated with abiraterone compared to enzalutamide-A pharmacovigilance study. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Current androgen receptor antagonists under investigation for resistant prostate cancer. [2022]

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

The Effect of Time to Castration Resistance on Outcomes With Abiraterone and Enzalutamide in Metastatic Prostate Cancer. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer. [2021]