ASCO GU 2023: EVOLUTION: Phase II Study of Radionuclide 177Lu-PSMA-617 Therapy Versus 177Lu-PSMA-617 in Combination with Ipilimumab and Nivolumab for Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC; ANZUP 2001)

( The 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 16th and 18th was host to a prostate cancer trials in progress poster session. Dr. Shahneen Sandhu presented the study design for the EVOLUTION trial, a phase II study of 177Lu-PSMA-617 in combination with ipilimumab and nivolumab versus 177Lu-PSMA-617 alone in patients with metastatic castration-resistant prostate cancer (mCRPC).

Dr. Sandhu began by noting that combination immune checkpoint inhibitors (ICI) in the form of ipilimumab and nivolumab have been shown to induce an adaptive immune response in patients with mCRPC. However, to date, clinical benefits have been modest at best. It has been hypothesized that radiation may modulate the tumor microenvironment, inducing an inflammatory response state that may enhance the activity of immune checkpoint inhibitors. In the EVOLUTION trial, the authors hypothesized that the combination of a radionuclide (177Lu-PSMA-617) and ICI (ipilimumab and nivolumab) may act synergistically, whereby 177Lu-PSMA-617 may induce immunogenic cell death enhancing the clinical efficacy of ipilimumab/nivolumab, leading to improved long-term clinical outcomes. EVOLUTION aims to determine the activity and safety of ipilimumab and nivolumab in combination with 177Lu-PSMA-617 in patients with mCRPC.

This trial is an open label, multicenter, phase II trial of patients with mCRPC with the following key eligibility criteria:

  • Progression on prior 2nd generation antiandrogen therapy
  • Have significant PSMA avidity on 68Ga-PSMA-11 PET/CT (SUVmax ≥15 at one disease site and SUVmax ≥10 at measurable sites of disease > 10 mm)
  • No FDG positive/PSMA negative disease, and no contraindications to ICI
  • Had received no more than one line of prior chemotherapy
  • No prior anti-PD1, anti-PD-L1/L2, anti-CTLA-4, or other checkpoint inhibitor therapy
  • No known active/suspected autoimmune disease
  • No conditions requiring systemic treatment with corticosteroids or other immunosuppressive medications
  • Adequate organ function and no intercurrent illness that might limit compliance with study treatment

The trial will randomize 100 patients in a 2:1 fashion to either the intervention arm of 177Lu-PSMA-617 7.5 GBq every 6 weeks for up to 6 doses plus ipilimumab 3 mg/kg every 6 weeks x 4 doses and nivolumab 1 mg/kg every 3 weeks x 8 doses during induction, followed by nivolumab 480 mg every 4 weeks x 18 doses during maintenance or 177Lu-PSMA-617 alone. Randomization will be stratified by study site and prior exposure to docetaxel. The primary endpoint is 12-month PSA progression-free survival. The study sample size of 100 patients will provide 90% power at an alpha/type 1 error rate of 0.1 to reject the null hypothesis of 1 year PSA-PFS of 20%, with an alternate hypothesis of 1 year PSA-PFS of 35%.

Secondary endpoints will include PSA response rate, adverse events, radiographic progression-free survival, overall survival, objective response rate, duration of response, and health-related quality of life. Correlative analysis will evaluate for potential prognostic/predictive biomarkers.


Patients will be evaluated every 3 to 4 weeks with clinical history/physical examination and blood tests. CT and bone scans will be performed at baseline and then every 12 weeks. Notably, patients will undergo both 68Ga-PSMA-11 and 18F FDG PET/CTs at baseline, following which a 68Ga-PSMA-11 PET/CT will be performed at week 24 and 177Lu-PSMA-617 SPECT/CT 24 hours after each 177Lu-PSMA-617 dose.


Translational analysis is planned using circulating tumor DNA (ctDNA) and peripheral blood mononuclear cells, which will be collected at baseline, weeks 13 and 25, and at radiographic progression. Optional fresh biopsies will be obtained at baseline, weeks 4-5, and at progression.

Study accrual began on October 11th, 2022, with the study currently active at 7 sites. As of February 1, 2023, 51 participants have been enrolled, with an estimated primary completion date of December 2024 (NCT05150236)

Presented by: Shahneen Sandhu, MBBS, FRACP, Associate Professor, Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.