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

Trial Summary

What is the purpose of this trial?

This trial tests if alternating high doses of testosterone and enzalutamide can help men with advanced prostate cancer better than just using enzalutamide alone. It targets men whose cancer has continued to progress despite standard treatments. The treatment works by first disrupting the cancer cells with high-dose testosterone, then blocking any remaining cancer cells from using testosterone with enzalutamide. Enzalutamide has been associated with improved overall survival in men with advanced prostate cancer.

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.

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

Research shows that Enzalutamide, when added to standard treatment, improves survival in men with metastatic hormone-sensitive prostate cancer and significantly enhances survival in castration-resistant prostate cancer. It also prolongs progression-free survival and has a high response rate in hormone-naïve prostate cancer. ^{1 2 3 4 5}

Is the combination of testosterone and enzalutamide safe for humans?

Enzalutamide, used for prostate cancer, is generally well-tolerated but can cause side effects like severe thrombocytopenia (low blood platelet count) and seizures. It has been shown to improve survival in men with castration-resistant prostate cancer. ^{3 6 7 8 9}

What makes the drug Enzalutamide unique for prostate cancer treatment?

Enzalutamide is unique because it is an oral drug that blocks multiple steps in the androgen receptor signaling pathway, which is crucial for the growth of prostate cancer cells. It has been shown to improve survival and delay disease progression in patients with metastatic castration-resistant prostate cancer, even in those who have not received chemotherapy. ^{1 10 11 12 13}

Research Team

Samuel Denmeade, M.D.

Principal Investigator

SKCCC at Johns Hopkins

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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 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 (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 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]

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 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]

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 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 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]

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]

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]

References

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

Enzalutamide Bests Older NSAAs in mHSPC. [2021]

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

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

3. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

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

5. Switzerland 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. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

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

7. Switzerland 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. [2023]

8. 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]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. [2022]

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

Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer. [2022]

11. Australia 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. [2021]

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

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

13. England pubmed.ncbi.nlm.nih.gov

An update on enzalutamide in the treatment of prostate cancer. [2020]