A Phase 3, Open-Label, Randomized Study Evaluating Metastatic Castrate Resistant Prostate Cancer Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment (SPLASH)

Official 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).

Eligibility Requirements

• Minimum Age: 18 Years
• Sex: MALE

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 455 participants

Study Arms

• Lead-in Dosimetry Phase: [Lu-177]-PNT2002 (EXPERIMENTAL)
  Participants received 6.8 gigabecquerels (GBq) (±10%) of \[Lu-177\]-PNT2002 by intravenous infusion every 8 weeks for 4 cycles.
• Randomization Phase: [Lu-177]-PNT2002 (Arm A) (EXPERIMENTAL)
  Participants received 6.8 GBq (±10%) of \[Lu-177\]-PNT2002 by intravenous infusion every 8 weeks for 4 cycles.
• Randomization Phase: Abiraterone or Enzalutamide (Arm B) (ACTIVE_COMPARATOR)
  Participants received either of below treatments until radiographic progression. * Enzalutamide 160 milligram (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 Blinded Independent Central Review (BICR) (or after final overall survival (OS), per local investigator-assessment), had not started an intervening treatment, and h
• Pharmacokinetic (PK) Extension Phase: [Lu-177]-PNT2002 (EXPERIMENTAL)
  Participants received 6.8 GBq (±10%) of \[Lu-177\]-PNT2002 by intravenous infusion every 8 weeks for 4 cycles.

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
• DRUG: Abiraterone — Abiraterone (1000 mg orally once daily with: 5 mg twice daily prednisone or 0.5 mg once daily dexamethasone)
• DRUG: Enzalutamide — Enzalutamide (160 mg orally once daily)

Primary Outcomes

• 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))

Secondary Outcomes

• Randomization Phase: Percentage of Participants With Objective Response Rate (ORR) (Randomization until measured progressive disease (up to 23 months))
• Randomization Phase: Duration of Response (From the date of first CR or PR to disease progression or death (up to 16.3 months))
• Randomization Phase: Percentage of Participants With Prostate-Specific Antigen (PSA) Response Rate (From the randomization up to 23 months)
• Randomization Phase: Biochemical Progression-Free Survival (bPFS) (From the randomization up to 23 months)
• Overall Survival (5 years)

Eligibility Criteria

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 tha

Trial Locations

• Arizona Institute of Urology (AIU) - Tucson, Tucson, Arizona, United States
• Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California, United States
• VA Greater Los Angeles Healthcare System, Los Angeles, California, United States
• University of California Los Angeles, Nuclear Medicine Clinic, Los Angeles, California, United States
• Hoag Memorial Hospital Presbyterian, Newport Beach, California, United States
• UC Irvine Chao Family Comprehensive Cancer Center, Orange, California, United States
• Stanford Cancer Institute, Palo Alto, California, United States
• University of Colorado Hospital, Aurora, Colorado, United States
• H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States
• University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
• ...and 10 more locations

Study Officials

• Jessica Jensen — STUDY_DIRECTOR
  Eli Lilly and Company

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