Will PSMAddition Deliver?

I’m thrilled to share a guest post by Dries Develtere as part of our “Let’s Get Ready for ESMO 2025!” series.
Timothée Olivier

Novartis announced that results from the PSMAddition trial will be presented at ESMO 2025. This open-label, phase III study evaluates the efficacy and safety of ¹⁷⁷Lu-PSMA-617 in combination with standard of care (SoC) versus SoC alone in adult men with metastatic hormone-sensitive prostate cancer (mHSPC).

SoC is defined as an androgen receptor pathway inhibitor (ARPI) plus androgen deprivation therapy (ADT). The primary endpoint is radiographic progression-free survival (rPFS), and the key secondary endpoint is overall survival (OS). Notably, crossover to ¹⁷⁷Lu-PSMA-617 after progression on SoC is allowed.

Novartis has already raised interest with a press release announcing “topline” results from an interim analysis, reporting a significant rPFS benefit and a “positive trend” in OS.

A Brief History of ¹⁷⁷Lu-PSMA-617 in Prostate Cancer

When a press release mentions a “positive trend” in OS, red flags should be raised. The enthusiasm surrounding ¹⁷⁷Lu-PSMA-617 is based on three key trials:

• TheraP (phase II): Patients with mCRPC progressing after docetaxel and ARPI were randomized to cabazitaxel (SoC) or ¹⁷⁷Lu-PSMA-617. The trial showed a significant PSA decline with ¹⁷⁷Lu-PSMA-617, but no OS benefit.

• VISION (phase III): Patients with mCRPC after docetaxel and ARPI were randomized to SoC or ¹⁷⁷Lu-PSMA-617. The trial was positive for both rPFS and OS, leading to FDA approval in the third-line setting. However, the exclusion of cabazitaxel from the control arm, and massive early dropouts from a suboptimal control arm, are questioning the validity of the OS benefit.

• PSMAfore (phase III): Conducted in the second-line setting after progression on one ARPI, comparing SoC (ARPI switch) with ¹⁷⁷Lu-PSMA-617. The trial met its rPFS endpoint but showed no OS benefit in the intention-to-treat analysis. Once again, the control arm (ARPI switch) was suboptimal.

In short: the only trial with a robust control arm (TheraP) showed no OS benefit, VISION was positive for OS but flawed, and PSMAfore failed to demonstrate an OS advantage even with a weak control arm.

What to Expect from PSMAddition

Despite these disappointing previous results, Novartis steps up its game and brings 177Lu-PSMA-617 to the front-line setting.

• Control arm: This time, the trial uses a better SoC comparator (ARPI + ADT). If positive, results have the potential to actually be practice-changing. However, how will the results apply to patients potentially candidate for triplet therapy?

• Patient population: Inclusion up to Eastern Cooperative Oncology Group (ECOG) 2 performance status broadens generalizability compared to most trials limiting to ECOG 0-1.

• Endpoints: rPFS as the primary, OS as key secondary. Given past data, rPFS will likely be positive. The press release already hints at no significant OS improvement, using the phrase “positive trend.”

• Safety: Expect the usual phrasing—“no new or unexpected safety signals,” “manageable adverse events.” The real questions are about high-grade toxicity, quality of life, and how many patients completed all six cycles.

• Crossover: This may be the most problematic aspect. While Novartis will argue that crossover is justified by VISION, the lack of OS benefit in PSMAfore undermines this rationale.

It’s important to understand why this undesirable crossover could skew results: patients who progress on SoC + 177Lu-PSMA-617 will get immediate access to docetaxel, which has been proven to improve survival in second line settings (here and here), which is not the case for 177Lu-PSMA-617.

In other words, patients who progress on SoC, and are offered 177Lu-PSMA-617, will have a delay in the exposure to docetaxel, which could lead to an artificial improvement in OS in the intervention arm (see a possible example of such phenomenom with Sipuleucel-T in this paper).

As a result, critical data will include:
○ How many patients crossed over versus receiving docetaxel?
○ Was there a difference between upfront versus post-progression use of ¹⁷⁷Lu-PSMA-617?

• Post-protocol therapy: Equally important is what happens after progression. Suboptimal post-trial care in the control group could exaggerate OS benefit in the intervention arm, while cumulative toxicity of ¹⁷⁷Lu-PSMA-617 might limit subsequent therapies. Transparent reporting here will be essential.

Conclusion

The PSMAddition trial represents a bold move by Novartis, pushing ¹⁷⁷Lu-PSMA-617 into the first-line setting. Yet, the history of this agent shows consistent rPFS gains without convincing OS benefit, because of lack of testing against robust comparators. With crossover allowed and OS already framed as a “trend,” some skepticism is warranted.

The critical questions at ESMO 2025 will be:

• Does ¹⁷⁷Lu-PSMA-617 truly improve OS in mHSPC?

• How did crossover and post-protocol therapies shape the results?

• And most importantly — will these data justify a shift in real-world first-line practice?

Dries Develtere, MD, is a Urologist at the General Hospital of Ypres, Belgium. He specializes in robotic surgery, with a focus on prostate and bladder procedures, as well as urological oncology. He is the founder of Surgical Vision, a video platform that provides high-quality surgical training videos designed to advance surgical education.