177Lu PSMA-617 Improves rPFS in mHSPC: PSMAddition Trial

3D rendered medically accurate illustration of prostate cancer: © SciePro - stock.adobe.com

Lutetium-177 (¹⁷⁷Lu) vipivotide tetraxetan (¹⁷⁷Lu PSMA-617; Pluvicto) in combination with hormone therapy provided a statistically significant and clinically meaningful benefit in radiographic progression-free survival (rPFS) in patients with prostate-specific membrane antigen (PSMA)-positive metastatic hormone-sensitive prostate cancer (mHSPC) compared with hormone therapy alone, according to findings from the interim analysis of the phase 3 PSMAddition trial (NCT04720157).¹

A promising trend in overall survival (OS) was also seen, positioning ¹⁷⁷Lu PSMA-617 as a potential new treatment in an earlier disease setting than its current approved indication. These data show the agents potential to potentially delay progression and improve long-term outcomes while maintaining a favorable safety profile.

¹⁷⁷Lu PSMA-617 is already an FDA-approved therapy for metastatic castration-resistant prostate cancer (mCRPC), with its efficacy established through the VISION (NCT03511664) and PSMAfore trials (NCT04689828).² This FDA approval for earlier use in mCRPC, based on the PSMAfore results, further underscores the drug's therapeutic value, and position ¹⁷⁷Lu PSMA-617 as the first radioligand therapy to be FDA approved for eligible patients with mCRPC.

“The progression from metastatic hormone-sensitive prostate cancer to castration-resistant disease remains a formidable challenge that can profoundly impact the survival of patients," said Shreeram Aradhye, MD, president of development and chief medical officer at Novartis, in a press release. "These results further strengthen our confidence in [¹⁷⁷Lu PSMA-617] as a PSMA-targeted radioligand therapy. Following the recent FDA approval based on the PSMAfore trial in metastatic castration-resistant prostate cancer, these data suggest using it in an earlier disease setting could advance care and address a significant unmet need for hormone-sensitive prostate cancer patients."

The positive readout from PSMAddition marks the third successful phase 3 trial for ¹⁷⁷Lu PSMA-617, reinforcing confidence in its mechanism as a PSMA-targeted radioligand therapy. This consistent performance across different disease stages suggests a broad applicability for ¹⁷⁷Lu PSMA-617 in prostate cancer management.

Novartis, the drug developer, plans to present the detailed results at an upcoming medical meeting and, following feedback from the FDA, will submit for regulatory review in the second half of the year.

About the PSMAddition Trial

The PSMAddition study is a phase 3, open-label, prospective, 1:1 randomized study designed to compare the efficacy and safety of ¹⁷⁷Lu PSMA-617 in combination with the standard of care (SOC) vs SOC alone in adult patients with PSMA-positive mHSPC. The SOC in this trial consists of a combination of androgen receptor pathway inhibitor therapy and androgen deprivation therapy.

Patients randomly assigned to the SOC alone arm are eligible to cross over to receive ¹⁷⁷Lu PSMA-617 upon confirmed radiographic progression by a blinded independent review committee (BIRC) and at the discretion of the treating physician. This crossover design ensures ethical considerations are met while still allowing for a robust assessment of ¹⁷⁷Lu PSMA-617’s benefits.

Enrollment was open to patients aged 18 years and older with an ECOG performance status of 0 to 2, a life expectancy of at least 9 months, metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma, and evidence of PSMA-positive disease as seen on a ⁶⁸Ga-PSMA-11 PET/CT scan. Additionally, patients were required to have at least 1 documented metastatic bone and/or soft tissue/visceral lesion documented within 28 days prior randomization, adequate organ function, and be treatment naive or have received minimal prior therapy.

This included up to 45 days of luteinizing hormone-releasing hormone (LHRH) agonists/antagonists or bilateral orchiectomy, with or without first-generation antiandrogens, for metastatic disease. Any such antiandrogen use needed to be discontinued before study therapy or within 45 days, whichever came first. Prior LHRH agonist/antagonist use in the adjuvant/neoadjuvant setting was permitted only if discontinued over 12 months prior to consent, did not exceed 24 months of therapy, and did not result in disease progression within 12 months of completion. Additionally, up to 45 days of CYP17 inhibitor or androgen receptor directed-therapy exposure for metastatic prostate cancer was allowed before consent, but no such exposure was permitted for earlier stages of prostate cancer.

The primary end point of the trial is rPFS, defined as the time to radiographic progression as assessed by BIRC using PCWG3-modified RECIST v1.1 criteria, or death from any cause. The key secondary end point is OS, measured as the time to death due to any cause. Additional secondary end points include progression-free survival, prostate-specific antigen 90 (PSA90) response, time to development of mCRPC, second PFS, overall response rate, disease control rate, duration of response, safety, and quality of life.³

REFERENCES:

1. Novartis Pluvicto™ demonstrates statistically significant and clinically meaningful rPFS benefit in patients with PSMA-positive metastatic hormone-sensitive prostate cancer. News release. Novartis. June 2, 2025. Accessed June 4, 2025. https://tinyurl.com/yk5ekt3c

2. Novartis Pluvicto approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA-positive metastatic castration-resistant prostate cancer. News release. Novartis. March 23, 2022. Accessed June 4, 2025. https://tinyurl.com/54h6x47b

3. An international prospective open-label, randomized, phase III study comparing 177Lu-PSMA-617 in combination with SoC, versus SoC alone, in adult male patients with mHSPC (PSMAddition). ClinicalTrials.gov. Updated March 5, 2025. Accessed June 4, 2025. https://www.clinicaltrials.gov/study/NCT04720157