Second Chances: The RE-LuPSMA Trial and Retreatment with Pluvicto
Phase 2 Prospective Trial of Retreatment with [177Lu]Lu-PSMA-617 Molecular Radiotherapy for Metastatic Castration-Resistant Prostate Cancer—RE-LuPSMA | Journal of Nuclear Medicine
The Problem: When Pluvicto Works, Then Stops Working
For men with advanced metastatic castration-resistant prostate cancer (mCRPC)—cancer that has spread beyond the prostate and no longer responds to standard hormone therapies—Pluvicto (lutetium Lu-177 vipivotide tetraxetan, or 177Lu-PSMA-617) has been a significant breakthrough. The FDA approved it in March 2022, and clinical trials have shown it extends overall survival and improves quality of life compared to standard treatments alone.[1][2]
But like many cancer therapies, there's a catch: Pluvicto is not a cure. Even men who respond well to an initial course of six cycles—sometimes experiencing remarkable declines in PSA and shrinkage of visible tumors—eventually see their disease recur. When that happens, the options become limited. They've already tried hormone therapies. They've often been through chemotherapy. They're looking at increasingly desperate choices.
That's where the RE-LuPSMA trial comes in.
The Idea: Try It Again
The clinical observation behind RE-LuPSMA is straightforward but important: some men who responded well to their first course of Pluvicto and tolerated it with acceptable side effects might benefit from a second course when their cancer progresses.
This isn't entirely new thinking. Over the past five years, researchers in Europe and the United States have published several small, retrospective studies (meaning they looked backward at patients' medical records) showing that patients retreated with 177Lu-PSMA-617 experienced PSA declines in 37% to 73% of cases—promising numbers, though with all the limitations of retrospective data.[3][4][5][6] These retreated patients also experienced predominantly blood-related side effects, with minimal kidney toxicity reported.[3]
The problem? No one had conducted a rigorous, prospective clinical trial to confirm that retreatment works reliably and safely. That's what makes RE-LuPSMA significant.
The RE-LuPSMA Trial: How It Works
Location: UCLA Ahmanson Translational Theranostics Division
Status: Currently recruiting
Trial ID: NCT06288113
Target Enrollment: 40 patients
Expected Completion: May 2028
Sponsor: UCLA/Jonsson Comprehensive Cancer Center
Financial Support: Novartis Pharmaceuticals
RE-LuPSMA is an open-label, single-arm phase 2 trial, meaning every participant knows they're receiving Pluvicto, and researchers are primarily focused on measuring outcomes rather than comparing to a control group. The trial enrolled its first patients in August 2024 and is actively recruiting.
Who can participate? Men with mCRPC who meet specific criteria:
- Age 18 or older
- Previously completed 4–6 cycles of Pluvicto
- Had a "favorable response" to that first course, defined as a PSA decline of at least 50%
- Their cancer has now progressed, as shown by a new PSMA PET/CT scan within 8 weeks before starting retreatment
- PSMA PET/CT scan shows at least one lesion with PSMA uptake; no large soft-tissue lesions that don't light up on the scan
- Adequate blood cell counts and kidney function (estimated glomerular filtration rate ≥ 50 mL/min)
What does participation involve? Participants receive up to six cycles of Pluvicto—the same dose and schedule as the first course: 7.4 GBq (essentially a standardized unit of radioactivity) intravenously every six weeks.
Beyond the infusions themselves, participants undergo regular monitoring:
- Blood tests twice per cycle to check cell counts, kidney function, and PSA levels
- SPECT/CT scans 24–72 hours after each infusion to measure how much radiation the kidneys receive (important for safety)
- PSMA PET/CT scans during weeks 3 of cycles 2, 4, and 6 to track tumor response
- Quality-of-life questionnaires about pain, fatigue, and overall well-being
- Long-term follow-up every six months for two years after the final treatment
The trial is designed to identify the maximum number of cycles each patient can safely receive without exceeding a kidney dose threshold of 39 Gray (a measure called biologically effective dose, or BED). The kidneys are the main organ of concern with Pluvicto, and this dosimetry-guided approach allows personalization of treatment.
The Primary Goal: Overall Survival at 12 Months
The trial's main question is straightforward: what percentage of men will be alive 12 months after starting retreatment?
The researchers hypothesized that 71% of retreated patients will survive to 12 months—compared to a baseline expectation of 50% from men receiving standard care alone (based on the VISION trial control arm).[1] This would represent roughly a 40% reduction in mortality risk. With 40 enrolled participants and a statistical power of 80%, the trial is designed to rigorously test this hypothesis.
Secondary endpoints include:
- Overall and severe adverse-event rates
- PSA response rate (≥50% PSA decline)
- Biochemical progression-free survival (time until PSA rises again by defined criteria)
- Radiographic progression-free survival (time until tumors progress on imaging)
- Pain response (for men with bone pain at baseline)
- Changes in quality-of-life scores and performance status
Why This Trial Matters
For men facing recurrence after an initial good response to Pluvicto, the stakes are high. They've already explored many treatment options. Retreatment with Pluvicto offers a glimmer of hope—a therapy they've proven they can tolerate, aimed at cancer they know will light up on a PSMA scan.
But glimmers aren't enough for formal treatment recommendations. Doctors and patients need prospective data: What percentage of men actually benefit? How often do serious side effects occur? How many cycles can be safely given? RE-LuPSMA is designed to answer those questions rigorously.
The trial also arrives at an important moment in Pluvicto's evolution. In March 2025, the FDA expanded Pluvicto's approval to include men who have received androgen receptor pathway inhibitors (ARPIs) but have not yet undergone chemotherapy.[7] This expansion, based on the PSMAfore trial, reflects growing confidence in the drug's benefit-to-risk profile in earlier-stage disease. Retreatment data will further expand the therapeutic toolkit available to oncologists.
The Safety Question: How Much Radiation Can the Kidneys Tolerate?
One of RE-LuPSMA's distinctive features is its careful attention to kidney dosimetry. The trial includes single-time-point SPECT/CT scans after every infusion—something requested specifically by the FDA—to track cumulative radiation dose to the kidneys.
Why? Lutetium-177 concentrates in the kidneys more than in most other organs (aside from salivary and lacrimal glands). Multiple researchers have established that a cumulative biologically effective dose to the kidneys of 39 Gray represents a reasonable safety threshold, based on experience with similar radioligand therapies.[8] If a patient is approaching this limit during retreatment, researchers can reduce or stop treatment to prevent serious kidney injury.
In the original VISION trial, which enrolled men after they'd already had chemotherapy, Grade 3 or 4 acute kidney injury occurred in only 3.4% of Pluvicto-treated patients.[1] In the more recent PSMAfore trial (men without prior chemotherapy), the kidney injury rate was even lower: 1.3%.[7] These are reassuring figures, but they reflect first-course treatment, not retreatment.
RE-LuPSMA will provide the first rigorous data on kidney safety in retreated patients.
What the Retrospective Data Show
Before RE-LuPSMA recruited its first participant, researchers had published four retrospective series on Pluvicto retreatment. A brief overview:
Yordanova et al. (2019) published one of the first reports, showing that 6 of 8 retreated patients had PSA declines of ≥50%, and myelotoxicity was the main toxicity observed.[3]
Gafita et al. (2019) reported on a larger cohort: 16 patients retreated with Pluvicto after an initial good response showed PSA response rates of 73%, with predominantly hematologic adverse events.[4]
Violet et al. (2020) presented longer follow-up data from 15 retreated patients compared to 21 patients who received a different next-line therapy. The retreated group had significantly higher PSA response rates and longer progression-free survival, leading one observer to note that "re-treatment may be an attractive option for suitable candidates."[5]
Most recent data (2024–2025): Rosar et al. and Santo et al. published prospective registry data showing PSA response rates of 40–60% in retreated patients, with predominantly hematologic toxicity and minimal kidney injury.[6][9] In June 2025, researchers presenting at the Society of Nuclear Medicine and Molecular Imaging Annual Meeting reported retreated patients achieving a median overall survival of 14.5 months, compared to 11.3 months in control arms of earlier trials.[10]
The common thread across these studies: retreatment appears to offer benefit (PSA response), is reasonably well tolerated (mostly blood-related side effects, minimal kidney injury), and deserves rigorous prospective evaluation.
Why Not Just Retreat Everyone?
A fair question. If retrospective data suggest retreatment can work, why conduct a prospective trial?
Retrospective studies have inherent limitations. Patients who were chosen for retreatment were likely selected because they did well initially and hadn't suffered serious toxicity—meaning they're probably not representative of all men with recurrence. Data collection may have been incomplete or inconsistent. Published series may reflect selection bias (positive results are more likely to be published than negative ones).
Moreover, retrospective data don't tell us about the threshold effects: at what rate of PSA response would we consider a treatment worthwhile? How much toxicity is acceptable? How many cycles can be safely given?
Prospective trials answer these questions systematically. They establish a baseline expectation, define success criteria before the trial begins, and report results transparently—including negative findings.
What Happens If RE-LuPSMA Shows Benefit?
If the trial reaches its primary endpoint (71% of men alive at 12 months), the clinical landscape for mCRPC could shift meaningfully. Current treatment guidelines would likely expand to include Pluvicto retreatment as an option for men who previously benefited and have recurrence.
For patients, this translates to additional time with a tolerable therapy rather than moving to chemotherapy or experimental regimens with higher toxicity profiles.
For the field, it validates a "rechallenge" approach that may apply to other targeted radiopharmaceuticals and cancer types in the future.
Are There Risks or Downsides?
Yes. Pluvicto carries known risks:
- Blood count drops (anemia, low platelets, low white blood cells) are common and sometimes severe enough to require treatment delay or dose reduction
- Kidney injury can occur, though it's uncommon with proper monitoring and hydration
- Salivary gland toxicity (dry mouth) can affect quality of life
- Gastrointestinal side effects (nausea, vomiting) may occur
- Fatigue is reported by many patients
- Cumulative radiation dose is a concern with multiple courses; hence the BED monitoring
For retreated patients, these risks are somewhat unknown. Some may be more sensitive to toxicity on a second course. Others may tolerate it well. RE-LuPSMA will clarify the safety profile in this population.
Additionally, not all patients qualify for retreatment. You need:
- Good kidney function to begin with
- Adequate blood counts to start
- PSMA expression on repeat imaging (some men's cancers lose PSMA expression over time)
- Disease that has progressed without intervening therapies that might confound results
Who Should Consider Enrolling?
The trial is currently enrolling at UCLA's Ahmanson Translational Theranostics Division in Los Angeles. If you're interested in learning more, you can:
- Visit ClinicalTrials.gov and search for NCT06288113
- Contact UCLA's site coordinator directly (information available through the trial's ClinicalTrials.gov page)
- Discuss participation with your oncologist, who may help coordinate referral
Be aware that trials require commitment: regular visits, imaging, blood draws, and follow-up questionnaires. But for men in a difficult clinical position, the combination of a therapy they've proven they can tolerate and rigorous data collection to guide future treatment makes RE-LuPSMA a meaningful option.
The Bigger Picture: Personalized Radiopharmaceutical Therapy
RE-LuPSMA is part of a broader shift in prostate cancer care toward personalized, precision medicine. Rather than a one-size-fits-all approach, oncologists increasingly tailor therapy based on:
- PSMA expression (is the cancer visible on PSMA PET?)
- Individual response (did this patient benefit from earlier treatments?)
- Organ-specific tolerability (how much kidney or bone marrow stress can this patient tolerate?)
- Prior therapy exposure (what has the patient already received?)
Retreatment fits naturally into this framework. If a patient responded to Pluvicto once and tolerated it, why not consider it again if the alternative is chemotherapy or experimental agents?
This philosophy is reflected in the FDA's recent approvals as well. The March 2025 expanded indication for Pluvicto in chemotherapy-naïve men—a decision partly based on PSMAfore trial data—shows regulatory agencies are comfortable with earlier use of PSMA-directed therapies when PSMA expression is present.
Timeline and Next Steps
RE-LuPSMA began enrolling in August 2024 with an anticipated completion date of May 2028. The trial will need to follow all 40 enrolled patients for approximately two years after their final treatment to measure the primary endpoint (12-month overall survival) and durability of response.
Results will likely be presented at major oncology conferences (ASCO, ESMO, Society of Nuclear Medicine) in 2027–2028, with potential for publication in a high-impact journal shortly thereafter.
For men currently navigating recurrence after Pluvicto, the timeline is frustrating—answers won't arrive for a couple more years. But the trial's ongoing conduct sends an important signal: the field recognizes rechallenge as a plausible option, and generating rigorous evidence about it is a priority.
Final Thoughts
Cancer recurrence is never welcome news, but for men whose disease comes back after responding to Pluvicto, RE-LuPSMA offers something increasingly rare in oncology: a second chance with a therapy they already know.
The trial may not answer every question (how does concomitant hormone therapy affect retreatment? Do time intervals between courses matter? Can men safely receive more than six cycles?), but it provides crucial prospective data on whether rechallenge is a viable path forward.
For men considering enrollment—and for their doctors weighing options—RE-LuPSMA represents rigorous science in service of a practical question: when recurrence happens after a favorable initial response, is it worth trying again?
Verified Sources and Citations
This article represents a synthesis of published clinical trials, regulatory announcements, and peer-reviewed literature as of May 2026. Information is intended for educational purposes and should not substitute for discussion with an oncologist or medical team regarding individual treatment decisions. Stephen Botti, IEEE Senior Life Member, Informed Prostate Cancer Support Group.
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