Phase III Randomized Study of 177Lu-PSMA-617 Versus Androgen Receptor-Directed Therapy in Taxane-Naïve Metastatic Castration-Resistant Prostate Cancer
- Trial ID
- 2023-507772-50-00
- Protocol
- CAAA617B12302
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether treatment with **177Lu-PSMA-617** improves the time to radiographic progression by PCWG3-modified RECIST v1.1 or death in participants with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) compared to participants treated with androgen receptor-directed therapy (ARDT). This is clinically relevant as it aims to determine the efficacy of 177Lu-PSMA-617 in delaying disease progression or death, which could potentially offer a significant therapeutic advantage for patients with this aggressive form of prostate cancer.
Secondary objectives include:
- Evaluating whether 177Lu-PSMA-617 improves overall survival (OS) compared to ARDT.
- Estimating the time to radiographic progression by blinded independent central review (BICR) or death in participants who crossover to 177Lu-PSMA-617 after radiographic progression (rPFS2).
- Evaluating progression-free survival (PFS) and second progression-free survival (PFS2) by investigator's assessment.
- Assessing whether 177Lu-PSMA-617 improves biochemical response as detected by prostate-specific antigen (PSA) halving compared to ARDT.
- Evaluating the time to first symptomatic skeletal event (TTSE) and time to radiographic soft tissue progression compared to ARDT.
- Assessing the time to chemotherapy initiation and health-related quality of life (HRQoL) improvements with 177Lu-PSMA-617 compared to ARDT.
- Evaluating the safety and tolerability of 177Lu-PSMA-617.
Participants
The clinical trial involves a total of **177 participants** diagnosed with **PSMA-positive metastatic castration-resistant prostate cancer**. The study population is exclusively male, with an age range of **18 years and older**. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of adenocarcinoma of the prostate and a positive **68Ga-PSMA-11 PET/CT scan**. All participants are required to have a castrate level of serum/plasma testosterone and must have shown progression on prior second-generation androgen receptor-directed therapy (ARDT). The trial excludes female subjects and does not involve a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are in relatively good health despite their condition. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to assess the efficacy of **177LuPSMA-617** in improving the time to radiographic progression or death compared to ARDT in this specific patient group.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, multi-center study to evaluate the efficacy of **177Lu-PSMA-617** compared to a change of androgen receptor-directed therapy (ARDT) in men with progressive **PSMA-positive metastatic castration-resistant prostate cancer** (mCRPC). The primary objective is to assess whether treatment with 177Lu-PSMA-617 improves the time to radiographic progression or death compared to ARDT. The trial is expected to run from June 2021 to September 2025, with participant involvement lasting up to 52 weeks, depending on the treatment arm.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as adequate organ function, recovery from prior therapy toxicities, and a positive 68Ga-PSMA-11 PET/CT scan. Following randomization, participants will receive either 177Lu-PSMA-617 or a change in ARDT. The trial includes regular follow-up visits to monitor safety, efficacy, and disease progression, with assessments including radiographic imaging and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Early termination from the study may occur due to disease progression, unacceptable toxicity, withdrawal of consent, or at the discretion of the investigator. The primary endpoint is radiographic progression-free survival, while secondary endpoints include overall survival, time to soft tissue progression, and quality of life assessments. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable data to the treatment landscape of mCRPC.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Abiraterone Acetate** is utilized in the trial as a **film-coated tablet**. It is administered orally with a maximum daily dose of 1000 mg and a total dose not exceeding 1582 g over a treatment period of up to 52 weeks. This chemical substance is not a pediatric formulation and serves as a comparator in the study.
**Enzalutamide** is another comparator used in the trial, available in both **film-coated tablet** and **soft capsule** forms. It is also administered orally, with a maximum daily dose of 160 mg and a total dose of up to 253120 mg over a 52-week period. Like Abiraterone Acetate, Enzalutamide is a chemical substance and is not formulated for pediatric use.
The experimental treatment, **Locametz 25 micrograms kit for radiopharmaceutical preparation**, contains the active substance **Gozetotide**. It is provided as a **solution for injection** and administered intravenously. The maximum daily dose is 150 MBq, with the same total dose limit, and the treatment period is limited to 1 day. This chemical substance is used as a test product in the trial.
Another experimental treatment, **Pluvicto 1 000 MBq/mL solution for injection/infusion**, contains **Lutetium (177Lu) Vipivotide Tetraxetan**. This solution is administered intravenously, with a maximum daily dose of 7.4 GBq and a total dose of 44.4 GBq over a 36-week period. This product is categorized under various therapeutic radiopharmaceuticals and is used as a test product in the study.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of these treatments in men with progressive metastatic castrate-resistant prostate cancer, focusing on the time to radiographic progression or death.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **radiographic progression-free survival (rPFS)**, defined as the time from randomization to the first documented radiographic disease progression or death from any cause, as assessed by blinded independent central review (BICR) following the Prostate Cancer Working Group 3 (PCWG3) Guidelines. Secondary endpoints include overall survival (OS), progression-free survival (PFS), and PFS2, which are measured from randomization to various progression events or death. Additionally, PSA50, the proportion of participants achieving a ≥50% decrease in PSA levels from baseline confirmed by a second measurement at least four weeks apart, will be evaluated at 3, 6, and 12 months.
Other secondary endpoints include time to symptomatic skeletal events (TTSSE), time to soft tissue progression (TTSTP), and time to chemotherapy (TTCT). Health-related quality of life (HRQoL) will be assessed using EQ-5D-5L, FACT-P, and BPI-SF instruments. The frequency of adverse events, safety laboratory assessments, and vital signs will also be monitored. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on patients with progressive metastatic castrate-resistant prostate cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent must be obtained prior to participation in the study
- Participants must be adults ≥ 18 years of age
- Participants must have an ECOG performance status of 0 to 1
- Participants must have histological pathological, and/or cytological confirmation of adenocarcinoma of the prostate
- Participants must be 68Ga-PSMA-11 PET/CT scan positive, and eligible as determined by the sponsor’s central reader
- Participants must have a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L)
- Participants must have progressed only once on prior second generation ARDT (abiraterone, enzalutamide, darolutamide, or apalutamide). first generation androgen receptor inhibitor therapy (e.g. bicalutamide) is allowed but not considered as prior ARDT therapy • second generation ARDT must be the most recent therapy received
- Participants must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria: • Serum/plasma PSA progression defined as 2 increases in PSA measured at least 1 week apart. The minimal start value is 2.0 ng/mL; 1.0 ng/mL is the minimal starting value if confirmed rise in PSA is the only indication of progression. • Soft-tissue progression defined [PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016)] • Progression of bone disease: two new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria (Scher et al 2016))
- Participants must have ≥ 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained prior to randomization
- Participants must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies (i.e. prior chemotherapy, radiation, etc.) except alopecia
- Participants must have adequate organ function: Bone marrow reserve: • ANC ≥ 1.5 x 109/L • Platelets ≥100 x 109/L • Hemoglobin ≥ 9 g/dL Hepatic: • Total bilirubin < 2 x the institutional upper limit of normal (ULN). For participants with known Gilbert’s Syndrome ≤ 3 x ULN is permitted • ALT or AST ≤ 3.0 x ULN OR ≤ 5.0 x ULN for participants with liver metastases Renal: • eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation
- Albumin ≥ 2.5 g/dL
- Candidates for change in ARDT as assessed by the treating physician • Participants cannot have previously progressed nor had intolerable toxicity to both enzalutamide and abiraterone.
Exclusion Criteria
- Previous treatment with any of the following within 6 months of randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation
- Any investigational agents within 28 days prior to day of randomization
- Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar classes
- Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy, or investigational therapy
- Transfusion or use of bone marrow stimulating agents for the sole purpose of making a participant eligible for study inclusion
- Participants with a history of CNS metastases who are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participants with CNS metastases are eligible if received therapy (surgery, radiotherapy, gamma knife), asymptomatic and neurologically stable without corticosteroids. Participants with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired.
- History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
- Any condition that precludes raised arms position
- Eligible for treatment(s) other than ARDT based on presence of any mutations or biomarkers that are known as predictors of better response (e.g., AR-V7 or BRCA).
- Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
- Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation. • HIV-infected participants who are at a low risk of AIDS-related outcomes may participate in this trial. • Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance).
- Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease free and treatment free for more than 3 years prior to randomization, are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer
- Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 14 weeks after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF
- Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: Participant with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed.
- History or current diagnosis of the following ECG abnormalities indicating significant risk of safety for study participants: • Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block) • History of familial long QT syndrome or known family history of Torsades de Pointe • Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, or CABG within 6 months prior to starting study treatment
- Previous PSMA-targeted radioligand therapy
- Prior treatment with cytotoxic chemotherapy for castration resistant or castrate sensitive prostate cancer (e.g., taxanes, platinum, estramustine, vincristine, methotrexate, etc.), immunotherapy or biological therapy [including monoclonal antibodies]. [Note: Taxane exposure (maximum 6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months have elapsed since completion of this adjuvant or neoadjuvant therapy. Prior treatment with sipuleucel-T is allowed]
- Not able to understand and to comply with study instructions and requirements
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 15 Jun 2021 | 9 |
 Belgium | Not Recruiting | 15 Jun 2021 | 16 |
 Czechia | Not Recruiting | 15 Jun 2021 | 15 |
 France | Not Recruiting | 15 Jun 2021 | 97 |
 Germany | Not Recruiting | 15 Jun 2021 | 6 |
 The Netherlands | Not Recruiting | 15 Jun 2021 | — |
 Slovakia | Not Recruiting | 15 Jun 2021 | 6 |
 Spain | Not Recruiting | 15 Jun 2021 | 154 |
 Sweden | Not Recruiting | 15 Jun 2021 | 10 |
| Netherlands | — | — | 21 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ABIRATERONE ACETATE | Comparator | — | ORAL USE | 1000 | 52 | SUB31647 |
ABIRATERONE ACETATE | Comparator | — | ORAL USE | 1000 | 52 | SUB31647 |
Pluvicto 1 000 MBq/mL solution for injection/infusion | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS | 7.4 | 36 | PRD10117050 |
ABIRATERONE ACETATE | Comparator | — | ORAL USE | 1000 | 52 | SUB31647 |
ENZALUTAMIDE | Comparator | — | ORAL USE | 160 | 52 | SUB77412 |
ENZALUTAMIDE | Comparator | — | ORAL USE | 160 | 52 | SUB77412 |
Locametz 25 micrograms kit for radiopharmaceutical preparation | Test | KIT FOR RADIOPHARMACEUTICAL PREPARATION | INTRAVENOUS | 150 | 1 | PRD10117083 |
ENZALUTAMIDE | Comparator | — | ORAL USE | 160 | 52 | SUB77412 |