Efficacy and Tolerability of Low-Dose Enzalutamide in Prostate Cancer (LODE)

Efficacy and Tolerability of Low-Dose Versus Standard-Dose Enzalutamide in Advance Prostate Cancer: a Real-World Evidence Study

Prostate cancer is the most common cancer in men in the United States and the second leading cause of cancer-related mortality in males. Since 2014, its incidence has increased by 3% annually, primarily due to a rise in advanced-stage cases. In Italy, over 41.000 cases were diagnosed in 2023, with 8.200 deaths. Enzalutamide, an androgen receptor inhibitor, is effective in treating metastatic prostate cancer but often requires dose reductions to improve tolerability in frail patients. Recent studies have shown that lower doses (≤ 80 mg per day) can maintain efficacy while improving safety and tolerability, with outcomes comparable to the standard dose (160 mg per day) in terms of overall survival, progression-free survival, and prostate-specific antigen response.

Based on the results observed in these studies, the investigators expect that in our retrospective cohort of patients with metastatic prostate cancer, those who received low doses of enzalutamide will have a 1 year progression-free survival comparable to the full dose. The investigators will also expect a lower rate of adverse events.

Study Overview

• Status: Not yet recruiting
• Conditions: Prostate Cancer Metastatic Disease

Detailed Description

Prostate cancer is the most frequent cancer in males in the United States, with 299.000 new cases estimated in 2024, and it is the second leading cause of cancer-related death in men. Since 2014, the prostate cancer incidence rate has risen by 3% per year, mostly driven by 4-5% per year increases for regional-stage and distant-stage diagnoses that began as early as 2011. Localized-stage disease also increased from 73.5 per 100.000 in 2014 to 84.8 per 100.000 in 2019, although the trend is not yet statistically significant. A recent study estimated that more than one half of men in the United States living with metastatic prostate cancer were initially diagnosed with localized or regional stage disease. In Italy, there were more than 41.000 diagnosed cases in 2023 and 8.200 deaths, accounting for nearly one-fifth of all cancers detected in men, and over 560.000 prevalent cases of men living with prostate.

Enzalutamide is a new generation oral androgen-receptor selective inhibitor that induces tumor regression and growth suppression in patients with metastatic prostate cancer. It is effective and well tolerated, compared with other anticancer drugs (ex-chemotherapy), but in real practice, very often in patients with comorbidity or poor performance status is necessary reduce the dose to reduce fatigue or other adverse events.

The standard recommended dosage of 160 mg per day has multiple side effects and dose reductions are often required.

Several randomized studies have underscored the importance of enzalutamide in treating prostate cancer. Initially approved by the Food and Drug Administration in 2012 for patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, its indications were updated in October 2020 to include patients with castration-resistant prostate cancer experiencing biochemical relapse, or with metastatic castration-sensitive prostate cancer.

In phase I study enzalutamide (MDV3100) was administered with dose between 30 and 600 mg per day. There was a linear increase in steady state serum concentration with dose, but antitumor effects were observed at all doses, including 40-60 mg per day. The severity of treatment related adverse effects including fatigue and neurological disorders was associated with drug dose.

Recent data suggest its efficacy may be retained at lower doses with significant improvement in safety and tolerability. In two previously observational studies, in metastatic prostate cancer low-dose enzalutamide (≤ 80 mg per day) compared to standard dose (160 mg per day) did not show difference in overall survival and prostate-specific antigen progression-free survival. Interestingly, there was a trend towards a better prostate-specific antigen response and a significantly longer life among the low-dose group.

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Monica Boitano; Phone Number: 00390105634505; Email: monica.boitano@galliera.it
• Study Contact Backup: Name: Martino Oliva; Phone Number: 00390105634506; Email: martino.oliva@galliera.it

Study Locations

• Italy
  • Genoa, Italy, 16128
    • Ente Ospedaliero Ospedali Galliera
    • Contact: Martino Oliva; Phone Number: +390105634506; Email: martino.oliva@galliera.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population will consist of male patients aged 18 years or older with a histopathological diagnosis of metastatic prostate cancer who received Enzalutamide between 01/08/2014 and 31/12/2023.

Description

Inclusion Criteria:

• Patients with histological diagnosis metastatic prostate cancer;
• Enzalutamide therapy taken between 01/08/2014 and 31/12/2023;
• Age ≥ 18 years;
• Signed Informed consent.

Exclusion Criteria:

• Clinically significant cardiovascular disease for example cerebrovascular accidents (<=6 months), myocardial infarction (<=3 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF); uncontrolled hypertension or bradycardia
• Patients who died within one month of starting treatment with Enzalutamide for all causes;
• Uncontrolled concomitant diseases.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Low Dose of Enzalutamide; Low Dose of Enzalutamide: ≤ 50% of the standard dose
High Dose of Enzalutamide; High Dose of Enzalutamide: > 80% of the standard dose
Intermediate Dose of Enzalutamide; Intermediate Dose of Enzalutamide: > 50% and ≤ 80% of the standard dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	The primary objective of this retrospective observational study is to evaluate whether low or intermediate doses of enzalutamide are comparable to the full dose in terms of 1-year average progression free survival time from the start of treatment, considering the event as the pathological progression of the disease.	1 year
Adverse events	To evaluate the rate of adverse events worsening between low, intermediate and full dose groups. As adverse events, fatigue, hypertension and neurological disorders will be assessed as adverse events of special interest.	At end of treatment with Enzalutamide

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	To evaluate the Overall Survival, in terms of 1 year average survival time from the start of treatment, between low or intermediate doses compared to full dose;	1 year
Overall Survival	To evaluate the Overall Survival (OS), in terms of 3-years average survival time from the start of treatment, between low or intermediate doses compared to full dose;	3 years
Prostate Specific Antigen response	To evaluate the Prostate Specific Antigen response at 12 weeks between groups.	3 months

Collaborators and Investigators

• Sponsor: Monica Boitano
• Investigators: Study Chair: Andrea De Censi, Ente Ospedaliero Ospedali Galliera

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2025
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: December 2, 2024
• First Submitted That Met QC Criteria: December 2, 2024
• First Posted (Actual): December 5, 2024

Study Record Updates

• Last Update Posted (Actual): July 16, 2025
• Last Update Submitted That Met QC Criteria: July 11, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Elderly; Metastatic prostate cancer; Enzalutamide; Adverse event; Prostatic neoplasms; Low-Doses
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Pathologic Processes; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Neoplastic Processes; Prostatic Neoplasms; Neoplasm Metastasis
• Other Study ID Numbers: LODE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No