Enzalutamide + Standard Therapy for Prostate Cancer

(DIRECT Trial)

Recruiting at 1 trial location

Overseen By Andrew McPartlin, MD

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must be taking: Hormone therapy

Disqualifiers: Significant comorbidities, Recent malignancy, others

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

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

Compensation: Varies

Number of Visits: 2

Duration: 8-9 months

132 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding abiraterone to standard treatments can improve the quality of life for prostate cancer patients. Participants will be divided into two groups: one will receive standard radiation and hormone therapy (also known as androgen suppression therapy or ADT), while the other will receive the same treatment plus abiraterone, taken daily by mouth. This research targets patients with prostate cancer that has spread to a limited number of areas and was diagnosed within the past six months. Participants should have prostate cancer sensitive to hormone therapy and should not be continuously using hormone treatment. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that enzalutamide, when combined with treatments like leuprolide, is generally safe. One study found that using enzalutamide with leuprolide reduced the risk of death by 40% compared to leuprolide alone, indicating its effectiveness without causing many additional issues for patients.

Another study involving over 2,000 patients found that enzalutamide reduced the risk of death by 33% compared to those not taking it. This study also assessed safety concerns, such as heart problems, and found that patients generally tolerated enzalutamide well.

While these results are promising, individual experiences may vary. The studies suggest that enzalutamide can be an effective and relatively safe option for many, but discussing personal concerns with a healthcare provider is always advisable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for prostate cancer because it combines abiraterone with standard therapies like androgen deprivation therapy (ADT) and radiation. Abiraterone is a key player here, as it works by blocking the production of androgens, which fuel prostate cancer growth. This approach is different from standard treatments that typically focus on reducing androgen levels through injections alone. By adding abiraterone, there's potential for a more comprehensive attack on the cancer, possibly leading to better outcomes. This combination could offer patients a more robust treatment option, sparking hope for improved survival rates and quality of life.

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

Studies have shown that enzalutamide can greatly improve survival rates for prostate cancer patients. Specifically, it lowered the risk of death by 33% compared to those who did not take it. Regarding cancer progression, men taking enzalutamide were 61% less likely to experience worsening cancer. This trial will compare standard care treatments with and without enzalutamide. These findings strongly suggest that enzalutamide effectively treats prostate cancer. ^{1 4 5 6 7}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• ADT
• Enzalutamide
• Standard of Care SBRT

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.

How Is the Trial Designed?

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 European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Androgen Deprivation Therapy for:

• Prostate Cancer

Approved in United States as Androgen Deprivation Therapy for:

• Prostate Cancer

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+

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

Published Research Related to This Trial

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]

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]

Second-generation androgen receptor inhibitors, such as enzalutamide and abiraterone, have significantly transformed the treatment landscape for advanced prostate cancer, particularly in cases that are resistant to castration.

Ongoing research is focused on overcoming resistance mechanisms and optimizing treatment sequences, which may lead to improved survival outcomes for patients with advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current androgen receptor antagonists under investigation for resistant prostate cancer. Nigro, MC., Mollica, V., Marchetti, A., et al.[2022]

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 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 80 patients with metastatic castration-resistant prostate cancer, a shorter time to castration resistance during primary androgen deprivation therapy (ADT) was linked to poorer progression-free survival (PFS) and overall survival after starting treatment with abiraterone or enzalutamide.

Despite the association, the time to castration resistance was not an independent predictor of survival or prostate-specific antigen (PSA) response when analyzed with other factors, suggesting that while it may indicate initial treatment outcomes, it does not determine the effectiveness of subsequent AR-targeting therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Time to Castration Resistance on Outcomes With Abiraterone and Enzalutamide in Metastatic Prostate Cancer. Hung, J., Taylor, AR., Divine, GW., 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]

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. nejm.org nejm.org/doi/full/10.1056/NEJMoa2510310?query=featured_home

Improved Survival with Enzalutamide in Biochemically ... In this trial, enzalutamide plus leuprolide led to significantly longer overall survival than leuprolide alone among patients with castration- ...

3. 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 ...

4. 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 ...

5. xtandi.com xtandi.com/clinical-trials

Clinical Trial Results | XTANDI® (enzalutamide) Men taking XTANDI had a 61% lower chance of their cancer progressing compared with men not taking XTANDI during the study. Progression was seen in 89 men (15.5 ...

6. pfizer.com pfizer.com/news/press-release/press-release-detail/xtandir-plus-leuprolide-reduced-risk-death-40-vs-leuprolide

XTANDI® Plus Leuprolide Reduced Risk of Death by 40% ... The probability of survival at 8 years was an unprecedented 78.9% with XTANDI plus leuprolide versus 69.5% with leuprolide, in men with ...

7. 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 ...