Metastatic Castration-Resistant Prostate Cancer
Conditions
Keywords
PSMA, mCRPC, Prostate cancer, 177Lu-PSMA, radioligand therapy, PSMA-I&T, SPLASH
Brief summary
The purpose of this study is to evaluate the efficacy and safety of \[Lu-177\]-PNT2002 in patients with metastatic castration-resistant prostate cancer who have progressed following treatment with androgen receptor axis-targeted therapy (ARAT).
Detailed description
The primary objective of the study is to determine the efficacy of \[Lu-177\]-PNT2002 (\[Lu-177\]-PSMA-I&T) versus abiraterone or enzalutamide in delaying radiographic progression in patients with mCRPC. The study consists of 3 phases: Dosimetry, Randomized Treatment, and Long term Follow up. The study will commence with a 25-patient safety and dosimetry lead-in (Part 1) and proceed to a randomization treatment phase in approximately 390 patients (Part 2). Patients in Part 2 will be randomized in a 2:1 ratio to receive either \[Lu-177\]-PNT2002 (Arm A), or enzalutamide or abiraterone (Arm B). Patients in Arm B who experience radiographic progression per central review and meet protocol defined eligibility, may crossover to receive \[Lu-177\]-PNT2002. After final overall survival (OS) analysis, all patients will continue to be followed through Continued Access, including long-term follow-up (LTFU) for at least 5 years from the first therapeutic dose, death, or loss to follow up (Part 3). Only patients that meet PSMA PET avidity criteria per central review will be eligible for this study.
Interventions
DRUG[Lu-177]-PNT2002
Participants randomized to Arm A will receive 6.8 GBq (±10%) of \[Lu-177\]-PNT2002 every 8 weeks for 4 cycles
DRUGAbiraterone
Abiraterone (1000 mg orally once daily with: 5 mg twice daily prednisone or 0.5 mg once daily dexamethasone)
DRUGEnzalutamide
Enzalutamide (160 mg orally once daily)
Sponsors
POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male aged 18 years or older. 2. Histological, pathological, and/or cytological confirmation of adenocarcinoma of the prostate. 3. Ineligible or averse to chemotherapeutic treatment options. 4. Patients must have progressive mCRPC at the time of consent based on at least 1 of the following criteria: 1. Serum/plasma PSA progression defined as increase in PSA greater than 25% and \>2 ng/mL above nadir, confirmed by progression at 2 time points at least 3 weeks apart. 2. Soft-tissue progression defined as an increase ≥20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or a new lesion. 3. Progression of bone disease defined as the appearance of two or more new lesions by bone scan. 5. Progression on previous treatment with one ARAT (abiraterone or enzalutamide or darolutamide or apalutamide) in either the CSPC or CRPC setting. 6. PSMA-PET scan (i.e., 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by the sponsor's central reader. 7. Castrate circulating testosterone levels (\<1.7 nmol/L or \<50 ng/dL). 8. Adequate organ function, independent of transfusion: 1. Bone marrow reserve: * i. White blood cell (WBC) count ≥2.5 × 10\^9/L OR absolute neutrophil count (ANC) ≥1.5 × 10\^9/L. * ii. Platelets ≥100 × 10\^9/L. * iii. Hemoglobin ≥8 mmol/L. 2. Liver function: * i. Total bilirubin ≤1.5 × institutional upper limit of normal (ULN). For patients with known Gilbert's syndrome, ≤3 × ULN is permitted. * ii. ALT or AST ≤3.0× ULN. 3. Renal function: * i. Serum/plasma creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min based on Cockcroft-Gault formula (for patients in France, serum/plasma creatinine ≤1.5 × ULN or CrCl ≥60 mL/min based on Cockcroft-Gault formula). 4. Albumin ≥30 g/L. 9. Human immunodeficiency virus-infected patients who are healthy and have a low risk of acquired immunodeficiency syndrome-related outcomes are included in this trial. 10. For patients who have partners who are pregnant or of childbearing potential: a condom is required along with a highly effective contraceptive method during the study and for 6 months after last study drug administration. Such methods deemed highly effective include a) combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, b) progestogen-only hormonal contraception associated with inhibition of ovulation, c) intrauterine device (IUD), d) intrauterine hormone-releasing system (IUS), e) bilateral tubal occlusion, f) vasectomy, g) true sexual abstinence: when this is in line with the preferred and usual lifestyle of the subject \[periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to IMP, and withdrawal are not acceptable methods of abstinence\]. 11. Willing to initiate ARAT therapy (either enzalutamide or abiraterone), pre-specified by investigator, if randomized to Treatment Arm B. 12. ECOG performance status 0 to 1. 13. Willing and able to comply with all study requirements and treatments (including 177Lu PNT2002) as well as the timing and nature of required assessments. 14. Signed informed consent.
Exclusion criteria
Patients are excluded from the study if any of the following criteria apply: 1. If noted in pathology report, prostate cancer with known significant (\>10% present in cells) sarcomatoid or spindle cell or neuroendocrine components. Any small cell component in the cancer should result in exclusion. 2. Prior treatment for prostate cancer ≤28 days prior to randomization, with the exclusion of first-line local external beam, ARAT, luteinizing hormone-releasing hormone (LHRH) therapy, or non-radioactive bone-targeted agents. 3. Any prior cytotoxic chemotherapy for CRPC (e.g., cabazitaxel or docetaxel); chemotherapy for hormone-sensitive prostate cancer (HSPC) is allowed if the last dose was administered \>1 year prior to consent. 4. Prior treatment with systemic radionuclides (e.g. radium-223, rhenium-186, strontium 89). 5. Prior immuno-therapy, except for sipuleucel-T. 6. Prior PSMA-targeted radioligand therapy, e.g., Lu-177-PSMA-617, I 131-1095. 7. Prior poly ADP ribose polymerase (PARP) inhibitor for prostate cancer. 8. Patients who progressed on 2 or more lines of ARATs. 9. Patients receiving bone-targeted therapy (e.g. denosumab, zoledronic acid) not on stable doses for at least 4 weeks prior to randomization. 10. Administration of an investigational agent ≤60 days or 5 half-lives, whichever is shorter, prior to randomization. 11. Major surgery ≤30 days prior to randomization. 12. Estimated life expectancy \<6 months as assessed by the principal investigator. 13. Presence of liver metastases \>1 cm on abdominal imaging. 14. A superscan on bone scan defined as a bone scan that demonstrates markedly increased skeletal radioisotope uptake relative to soft tissues in association with absent or faint genitourinary tract activity. 15. Dose escalation or initiation of opioids for cancer-related pain ≤30 days prior to consent up to and including randomization. 16. Known presence of central nervous system metastases. 17. Contraindications to the use of planned ARAT therapy, \[Ga-68\]-PSMA-11, \[F-18\]-DCFPyL or \[Lu-177\]-PNT2002 therapy, including but not limited to the following: * Hypersensitivity to \[Ga-68\]-PSMA-11, \[F-18\]-DCFPyL or \[Lu-177\]-PNT2002 excipients (Diethylenetriaminepentaacetic acid (DTPA), Sodium ascorbate, Lascorbic acid, Sodium gentisate, HCl, Sodium hydroxide). * Recent myocardial infarction or arterial thrombotic events (in the past 6 months) or unstable angina (in the past 3 months), bradycardia or left ventricular ejection fraction measurement of \< 50%. * History of seizures in patients planned to receive enzalutamide. 18. Active malignancy other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer. 19. Concurrent illness that may jeopardize the patient's ability to undergo study procedures. 20. Serious psychological, familial, sociological, or geographical condition that might hamper compliance with the study protocol and follow-up schedule. Patients that travel need to be capable of repeated visits even if they are on the control arm. 21. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression. 22. Concurrent serious (as determined by the investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure (see 12.1 Appendix 1), unstable ischemia, uncontrolled symptomatic arrhythmia, 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Randomization Phase: Radiographic Progression-Free Survival (rPFS) | From the randomization date to the first documented progressive disease or death from any cause (up to 23 months) | * rPFS, as assessed by blinded independent central review (BICR), is the time from the randomization date to progression on soft tissue per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or confirmed progression on bone lesions by Prostate Cancer Working Group 3 (PCWG3) criteria, or death from any cause. * The date of disease progression is the date of the scan for the first objectively documented progressive disease (PD) per RECIST v1.1 or PCWG3. PD is defined as a ≥20% increase in the sum of the diameters of target lesions (≥5 mm absolute), with reference being the smallest sum in the study, or unequivocal progression of non-target lesions, or appearance of new lesions. * Participants who do not progress, including those who started new anticancer therapy, withdrew from the study, or were lost to follow-up without disease progression, were censored at the last valid assessment for RECIST v1.1 or PCWG3. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Randomization Phase: Percentage of Participants With Objective Response Rate (ORR) | Randomization until measured progressive disease (up to 23 months) | * ORR, as assessed by BICR, is the best confirmed overall tumor response of complete response (CR) or partial response (PR) as per RECIST v1.1 ( in the absence of confirmed progression on bone scan assessed by PCWG3). * CR is a disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). * PR is at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), without progression of non-target lesions or appearance of new lesions. |
| Randomization Phase: Duration of Response | From the date of first CR or PR to disease progression or death (up to 16.3 months) | Duration of Response, as assessed by BICR, is the time from the date of first documented confirmed CR or PR as per RECIST v1.1 (in the absence of confirmed progression on bone scan assessed by PCWG3) to the date of first documented radiographic progression or death in the absence of progression. Participants who have attained CR or PR as the best overall response, did not have progressive disease, and did not die will be censored. |
| Randomization Phase: Percentage of Participants With Prostate-Specific Antigen (PSA) Response Rate | From the randomization up to 23 months | The PSA response rate, as per the PCWG3 criteria, is the percentage of participants achieving a ≥50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second PSA assessment conducted at least 3 weeks later. |
| Randomization Phase: Biochemical Progression-Free Survival (bPFS) | From the randomization up to 23 months | bPFS is the time from the date of randomization to the date of the first PSA increase from baseline ≥25% and ≥2 nanograms per milliliter (ng/mL) above nadir confirmed by a second PSA measurement defining progression ≥3 weeks later, as per PCWG3, or death from any cause in the absence of progression. Participants who do not progress or die including those who withdraw from the study or are lost to follow-up will be censored at the time of last valid PSA measurement. |
| Overall Survival | 5 years | Time from the date of randomization until death due to any cause. |
Countries
Canada, France, Netherlands, Sweden, United Kingdom, United States
Participant flow
Recruitment details
The study includes: * Lead-in dosimetry phase to evaluate the dosimetry of \[Lu-177\]-PNT2002 across standard organs such as the kidneys, salivary and lacrimal glands. * Randomization phase to compare the efficacy of \[Lu-177\]-PNT2002 versus enzalutamide or abiraterone (control arm). Additionally, there is a pharmacokinetic (PK) extension phase, in which participants were enrolled at selected sites in the United States and Canada for PK assessments of \[Lu-177\]-PNT2002.
Pre-assignment details
(continued.,) Participants were unique to each phase of the study, those participated in one phase did not transition to any other phase. All participants will be followed in the long-term follow-up phase for at least five years from the date of their first therapeutic dose, or until death or loss to follow-up, whichever occurs first.
Participants by arm
| Arm | Count |
|---|---|
| Lead-in Dosimetry Phase: [Lu-177]-PNT2002 Participants received 6.8 GBq (±10%) of \[Lu-177\]-PNT2002 by intravenous infusion every 8 weeks for 4 cycles. | 27 |
| Randomization Phase: [Lu-177]-PNT2002 (Arm A) Participants received 6.8 GBq (±10%) of \[Lu-177\]-PNT2002 by intravenous infusion every 8 weeks for 4 cycles. | 276 |
| Randomization Phase: Abiraterone or Enzalutamide (Arm B) Participants received either of below treatments until radiographic progression.
* Enzalutamide 160 mg orally once daily (or)
* Abiraterone 1000 mg orally once daily coadministered with prednisone 5 mg orally twice daily or dexamethasone 0.5 mg orally once daily.
Participants who experienced radiographic progression per BICR (or after final OS, per local investigator-assessment), had not started an intervening treatment, and had no uncontrolled AEs were eligible to consent to cross over to receive 6.8 GBq (±10%) of \[Lu-177\]-PNT2002 intravenous infusion every 8 weeks for 4 cycles. | 136 |
| PK Extension Phase: [Lu-177]-PNT2002 Participants received 6.8 GBq (±10%) of \[Lu-177\]-PNT2002 by intravenous infusion every 8 weeks for 4 cycles. | 16 |
| Total | 455 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 13 | 76 | 32 | 0 |
| Overall Study | Incorrect enrollment | 0 | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 | 0 |
| Overall Study | Ongoing | 9 | 183 | 93 | 15 |
| Overall Study | Physician Decision | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 15 | 8 | 1 |
Baseline characteristics
| Characteristic | Lead-in Dosimetry Phase: [Lu-177]-PNT2002 | Randomization Phase: [Lu-177]-PNT2002 (Arm A) | Randomization Phase: Abiraterone or Enzalutamide (Arm B) | PK Extension Phase: [Lu-177]-PNT2002 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 20 Participants | 224 Participants | 109 Participants | 16 Participants | 369 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 52 Participants | 27 Participants | 0 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 5 Participants | 1 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 262 Participants | 129 Participants | 15 Participants | 432 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 12 Participants | 2 Participants | 0 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 11 Participants | 2 Participants | 0 Participants | 13 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 32 Participants | 8 Participants | 1 Participants | 45 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 16 Participants | 12 Participants | 0 Participants | 28 Participants |
| Race (NIH/OMB) White | 23 Participants | 215 Participants | 112 Participants | 15 Participants | 365 Participants |
| Region of Enrollment Canada | 12 Participants | 78 Participants | 42 Participants | 1 Participants | 133 Participants |
| Region of Enrollment France | 0 Participants | 25 Participants | 15 Participants | 0 Participants | 40 Participants |
| Region of Enrollment Netherlands | 0 Participants | 11 Participants | 6 Participants | 0 Participants | 17 Participants |
| Region of Enrollment Sweden | 0 Participants | 3 Participants | 5 Participants | 0 Participants | 8 Participants |
| Region of Enrollment United Kingdom | 0 Participants | 10 Participants | 3 Participants | 0 Participants | 13 Participants |
| Region of Enrollment United States | 15 Participants | 149 Participants | 65 Participants | 15 Participants | 244 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 27 Participants | 276 Participants | 136 Participants | 16 Participants | 455 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 27 | 76 / 276 | 32 / 136 | 12 / 77 | 0 / 16 |
| other Total, other adverse events | 24 / 27 | 259 / 269 | 117 / 130 | 59 / 77 | 14 / 15 |
| serious Total, serious adverse events | 6 / 27 | 47 / 269 | 30 / 130 | 14 / 77 | 2 / 15 |
Outcome results
Primary
Randomization Phase: Radiographic Progression-Free Survival (rPFS)
* rPFS, as assessed by blinded independent central review (BICR), is the time from the randomization date to progression on soft tissue per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or confirmed progression on bone lesions by Prostate Cancer Working Group 3 (PCWG3) criteria, or death from any cause. * The date of disease progression is the date of the scan for the first objectively documented progressive disease (PD) per RECIST v1.1 or PCWG3. PD is defined as a ≥20% increase in the sum of the diameters of target lesions (≥5 mm absolute), with reference being the smallest sum in the study, or unequivocal progression of non-target lesions, or appearance of new lesions. * Participants who do not progress, including those who started new anticancer therapy, withdrew from the study, or were lost to follow-up without disease progression, were censored at the last valid assessment for RECIST v1.1 or PCWG3.
Time frame: From the randomization date to the first documented progressive disease or death from any cause (up to 23 months)
Population: All participants from the ITT analysis set. Number of participants censored in \[Lu-177\]-PNT2002 (Arm A)=114, Abiraterone or Enzalutamide (Arm B)=40. The Overall Number of Participants Analyzed reported is inclusive of the censored participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomization Phase: [Lu-177]-PNT2002 (Arm A) | Randomization Phase: Radiographic Progression-Free Survival (rPFS) | 9.5 months |
| Randomization Phase: Abiraterone or Enzalutamide (Arm B) | Randomization Phase: Radiographic Progression-Free Survival (rPFS) | 6.0 months |
p-value: 0.008895% CI: [0.55, 0.92]Log Rank
Secondary
Overall Survival
Time from the date of randomization until death due to any cause.
Time frame: 5 years
Secondary
Randomization Phase: Biochemical Progression-Free Survival (bPFS)
bPFS is the time from the date of randomization to the date of the first PSA increase from baseline ≥25% and ≥2 nanograms per milliliter (ng/mL) above nadir confirmed by a second PSA measurement defining progression ≥3 weeks later, as per PCWG3, or death from any cause in the absence of progression. Participants who do not progress or die including those who withdraw from the study or are lost to follow-up will be censored at the time of last valid PSA measurement.
Time frame: From the randomization up to 23 months
Population: All participants from the ITT analysis set. Number of participants censored in \[Lu-177\]-PNT2002 (Arm A)=133, Abiraterone or Enzalutamide (Arm B)=54. The Overall Number of Participants Analyzed reported is inclusive of the censored participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomization Phase: [Lu-177]-PNT2002 (Arm A) | Randomization Phase: Biochemical Progression-Free Survival (bPFS) | 7.0 months |
| Randomization Phase: Abiraterone or Enzalutamide (Arm B) | Randomization Phase: Biochemical Progression-Free Survival (bPFS) | 3.9 months |
Secondary
Randomization Phase: Duration of Response
Duration of Response, as assessed by BICR, is the time from the date of first documented confirmed CR or PR as per RECIST v1.1 (in the absence of confirmed progression on bone scan assessed by PCWG3) to the date of first documented radiographic progression or death in the absence of progression. Participants who have attained CR or PR as the best overall response, did not have progressive disease, and did not die will be censored.
Time frame: From the date of first CR or PR to disease progression or death (up to 16.3 months)
Population: All participants from the ITT analysis set who had achieved confirmed CR or PR responses (ORR). Number of participants censored in \[Lu-177\]-PNT2002 (Arm A)=18, Abiraterone or Enzalutamide (Arm B)=1. The Overall Number of Participants Analyzed reported is inclusive of the censored participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomization Phase: [Lu-177]-PNT2002 (Arm A) | Randomization Phase: Duration of Response | 9.4 months |
| Randomization Phase: Abiraterone or Enzalutamide (Arm B) | Randomization Phase: Duration of Response | 8.3 months |
Secondary
Randomization Phase: Percentage of Participants With Objective Response Rate (ORR)
* ORR, as assessed by BICR, is the best confirmed overall tumor response of complete response (CR) or partial response (PR) as per RECIST v1.1 ( in the absence of confirmed progression on bone scan assessed by PCWG3). * CR is a disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). * PR is at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), without progression of non-target lesions or appearance of new lesions.
Time frame: Randomization until measured progressive disease (up to 23 months)
Population: All participants from the ITT analysis set who had measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomization Phase: [Lu-177]-PNT2002 (Arm A) | Randomization Phase: Percentage of Participants With Objective Response Rate (ORR) | 32.0 percentage of participants |
| Randomization Phase: Abiraterone or Enzalutamide (Arm B) | Randomization Phase: Percentage of Participants With Objective Response Rate (ORR) | 8.0 percentage of participants |
Secondary
Randomization Phase: Percentage of Participants With Prostate-Specific Antigen (PSA) Response Rate
The PSA response rate, as per the PCWG3 criteria, is the percentage of participants achieving a ≥50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second PSA assessment conducted at least 3 weeks later.
Time frame: From the randomization up to 23 months
Population: All participants from the ITT analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomization Phase: [Lu-177]-PNT2002 (Arm A) | Randomization Phase: Percentage of Participants With Prostate-Specific Antigen (PSA) Response Rate | 30.1 percentage of participants |
| Randomization Phase: Abiraterone or Enzalutamide (Arm B) | Randomization Phase: Percentage of Participants With Prostate-Specific Antigen (PSA) Response Rate | 12.5 percentage of participants |