Sequential Testosterone + Enzalutamide for Prostate Cancer

Recruiting at 5 trial locations

Overseen By GU oncology

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must be taking: Androgen ablative therapy

Must not be taking: Enzalutamide, Apalutamide

Disqualifiers: Pain, Uncontrolled infection, Anticoagulation, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 56

Duration: Up to 2 years

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating prostate cancer that has spread and stopped responding to some standard treatments. Researchers aim to determine if alternating high-dose testosterone shots (such as testosterone cypionate or testosterone enanthate) with the drug enzalutamide can better control the cancer compared to using enzalutamide alone. The trial is open to those with prostate cancer that has spread but isn't causing pain and who have previously tried certain treatments without success. This might be suitable for individuals who have undergone specific prostate cancer treatments but are experiencing disease progression. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

You will need to stop taking abiraterone at least 2 weeks before starting the trial. Attempts should be made to reduce or stop prednisone, but if symptoms persist, you may continue on the lowest dose possible. If you are on warfarin, rivaroxaban, or apixaban, you must switch to enoxaparin before starting the trial.

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

Research has shown that enzalutamide, a treatment for prostate cancer, is generally safe, with most patients tolerating it well. Possible side effects include fatigue and high blood pressure, though serious issues are rare.

Regarding testosterone cypionate, research has not established a direct link to increased prostate cancer risk. However, there is a small chance of heart-related issues, particularly for men with a history of heart problems, so monitoring is important.

Overall, many patients have safely used both treatments. Consulting a doctor is crucial to understand the risks and benefits for each specific situation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for prostate cancer because they explore a unique approach of alternating testosterone with enzalutamide, potentially offering a new way to manage the disease. Unlike traditional treatments that might rely solely on continuous enzalutamide, this approach leverages cycles of high-dose testosterone injections to potentially enhance the effectiveness of enzalutamide. This method could offer a fresh strategy by targeting cancer cells differently, potentially overcoming resistance and improving outcomes. The combination could provide a novel mechanism of action, alternating hormonal stimulation with inhibition to keep the cancer in check.

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

Research shows that using testosterone with enzalutamide can help treat prostate cancer. In this trial, participants in Arm B will receive sequential testosterone and enzalutamide, while those in Arm C will receive variable sequential testosterone and enzalutamide. Previous studies have shown that patients who received this combination lived longer, with an average survival of 37.1 months, compared to 28.6 months for those who only took enzalutamide. Early results suggest that switching between testosterone and enzalutamide might slow or stop tumor growth more effectively than using enzalutamide alone. This approach, called sequential therapy, is being studied as a promising option for men with advanced prostate cancer that no longer responds to standard hormone therapy.

Participants in Arm A will receive enzalutamide alone, which has also proven effective. It reduced the risk of death by 33% in prostate cancer patients. It also improved long-term survival rates and was better at preventing the disease from worsening compared to other treatments. Both treatments are being researched in this trial to find the best way to manage prostate cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Samuel Denmeade, M.D.

Principal Investigator

SKCCC at Johns Hopkins

Are You a Good Fit for This Trial?

Men over 18 with advanced prostate cancer that's worsened despite hormone therapy and possibly one round of chemotherapy. They must have no prior use of certain other cancer drugs, manageable pain levels, and be off steroids for a period. Major organ functions need to be within acceptable ranges, and they should not have had recent major surgery or serious health conditions that could affect their safety.

Inclusion Criteria

- Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 ×109/L)

My prostate cancer was confirmed through a tissue examination.

I am undergoing hormone therapy for cancer.

Exclusion Criteria

I use a catheter for urination due to prostate issues.

You have a serious medical, mental, or other condition that could make it unsafe for you to participate in the study or understand what it involves.

I haven't had major surgery in the last 3 weeks or still recovering from one.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either continuous Enzalutamide or sequential testosterone and Enzalutamide based on randomization

Up to 2 years

Every cycle (56 days) includes PSA level and symptoms assessment; bone/CT scans every 4 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term if beneficial

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Enzalutamide
• Testosterone cypionate
• Testosterone enanthate

Trial Overview The trial is testing if giving high doses of testosterone followed by Enzalutamide can slow down the progression of prostate cancer better than just continuous Enzalutamide. Men will be randomly assigned to either the sequential treatment group or the standard therapy group in an open-label setting.

How Is the Trial Designed?

Group I: Arm C: Variable Sequential Testosterone and Enzalutamide Experimental Treatment 3 Interventions

Patients in Arm C will receive intramuscular injection with testosterone cypionate (T) at a dose of 400 mg every 28 days x 2 injections per cycle. Each cycle is 56 days. Patients with PSA progression will stop T injection and begin Enzalutamide. Patients on T with initial PSA decline will remain on high dose T for additional cycles of 2 injections until PSA progression occurs (≥25% increase in PSA from PSA nadir on current BAT cycle). These patients will then be started on Enzalutamide. Patients with PSA progression will stop Enzalutamide and will restart injections of T with 2 injections/cycle. Patients on enzalutamide with initial PSA decline after one 56-day cycle will continue on Enzalutamide until PSA progression occurs (≥25% increase in PSA from PSA nadir on current Enzalutamide cycle). These cycles of switching between T and Enza with onset of PSA progression will continue until clinical and/or radiographic progression occurs.

Group II: Arm B: Sequential Testosterone and Enzalutamide Experimental Treatment 3 Interventions

Patients in Arm B will receive intramuscular injection with testosterone cypionate (T) at a dose of 400 mg every 28 days x 2 (i.e. cycle 1). On Day 1 of cycle 2, patients will stop testosterone and begin enzalutamide 160 mg po q day for 56 days. Each cycle is 56 days. On Day 1 of cycle 3, patient will not take enzalutamide and will again receive injection of testosterone. Patients will continue to alternate one cycle of testosterone (2 injections) with one cycle of 56 days of enzalutamide.

Group III: Arm A: Enzalutamide Experimental Treatment 1 Intervention

Patients randomized to Arm A will receive continuous therapy with standard dose Enzalutamide (160 mg oral daily).

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?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

Enzalutamide effectively inhibits androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) by blocking multiple steps, including androgen binding and nuclear translocation, without exhibiting AR agonistic activity, which is a significant advantage over bicalutamide.

In preclinical models, enzalutamide not only reduced tumor volume in CRPC xenografts but also induced apoptosis in prostate cancer cells, suggesting its potential as a powerful treatment option for patients with advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer. Guerrero, J., Alfaro, IE., Gómez, F., 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 a phase 2 study involving 60 patients with metastatic castration-resistant prostate cancer (mCRPC), enzalutamide treatment led to a significant decline in prostate-specific antigen (PSA) levels in 45% of patients, indicating its efficacy in managing this advanced cancer.

The study found that the presence of the androgen receptor variant ARV7 was linked to primary resistance to enzalutamide, suggesting that certain androgen signaling characteristics before treatment can predict patient response to the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. Efstathiou, E., Titus, M., Wen, S., 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]

Enzalutamide significantly improves survival and delays skeletal-related events in patients with metastatic castration-resistant prostate cancer (mCRPC), as shown in the phase III AFFIRM study with consistent benefits across all subgroups.

In the phase III PREVAIL study, enzalutamide reduced the risk of radiographic progression and death in chemotherapy-naïve mCRPC patients, while also demonstrating a favorable safety profile with similar adverse event rates compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on enzalutamide in the treatment of prostate cancer. Merseburger, AS., Haas, GP., von Klot, CA.[2020]

In a study involving 249 men with metastatic castrate-resistant prostate cancer, patient preference between darolutamide and enzalutamide was balanced, with no significant preference for either treatment (p = 0.92).

Darolutamide was associated with less fatigue and a moderate improvement in episodic memory compared to enzalutamide, suggesting it may offer a better quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA. Colomba, E., Jonas, SF., Eymard, JC., et al.[2023]

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 study of 198 chemotherapy-naïve patients with castration-resistant prostate cancer, the sequence of treatment with abiraterone followed by enzalutamide showed significantly better prostate-specific antigen (PSA) progression-free survival compared to the reverse sequence, indicating a potential advantage in treatment order.

While the abiraterone-to-enzalutamide sequence improved PSA progression-free survival, there was no significant difference in overall survival between the two treatment sequences, suggesting that while the order of medications may impact PSA levels, it does not necessarily affect overall patient survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring the optimal sequence of abiraterone and enzalutamide in patients with chemotherapy-naïve castration-resistant prostate cancer: The Kyoto-Baltimore collaboration. Terada, N., Maughan, BL., Akamatsu, S., 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]

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]

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 men with metastatic hormone-sensitive prostate cancer, enzalutamide, when combined with androgen-deprivation therapy, significantly prolonged radiographic progression-free survival compared to a placebo.

This finding highlights the efficacy of enzalutamide as an androgen-receptor inhibitor in improving outcomes for patients undergoing treatment for advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eyeing Enzalutamide for Hormone-Sensitive Prostate Cancer. [2020]

In a long-term study of 67 patients with hormone-naïve prostate cancer, enzalutamide monotherapy resulted in a 100% prostate-specific antigen (PSA) response rate at 97 weeks for those who remained on treatment, indicating its strong efficacy.

The treatment was well-tolerated with minimal negative effects on total-body bone mineral density, although common side effects included gynecomastia and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results. Tombal, B., Borre, M., Rathenborg, P., et al.[2021]

Citations

1. 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 ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2303974

Improved Outcomes with Enzalutamide in Biochemically ... In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with ...

3. 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) ...

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. 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 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01212991

NCT01212991 | A Safety and Efficacy Study of Oral ... The purpose of this study is to determine the benefit of enzalutamide versus placebo as assessed by overall survival and progression-free survival in patients ...

7. pfizer.com pfizer.com/news/press-release/press-release-detail/xtandir-plus-leuprolide-significantly-improves-survival

XTANDI® Plus Leuprolide Significantly Improves Survival ... XTANDI® Plus Leuprolide Significantly Improves Survival Outcomes in Men with Non-Metastatic Hormone-Sensitive Prostate Cancer with High-Risk ...

8. 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.