PLUVICTO® Before Chemotherapy: A New Option for Advanced Prostate Cancer

Overview

For oncologists familiar with PLUVICTO® and its use in prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC), the drug’s path to FDA approval has followed a somewhat predictable progression. Initially, PLUVICTO® was approved only for patients who had received androgen receptor pathway inhibitors (ARPI) and at least one taxane-based chemotherapy. As Dr. Munir Ghesani, Chief Medical Officer at United Theranostics, explains, “the design of the trial was such that there were a lot of competing treatment options at the time.” Suffice to say, many in the field were not surprised when the FDA approved PLUVICTO®’s use as a treatment for patients who had already received chemotherapy, and knew that the next stage of the drug’s approval would include use as treatment before chemotherapy, as demonstrated by the PSMAfore trial. Before considering why, it’s best to have an understanding of how treatment with PLUVICTO® works.

What Is PLUVICTO®, and Why Is It Different?

PLUVICTO® (Lutetium Lu-177 PSMA-617) is a targeted radiopharmaceutical therapy (RPT), meaning that it can target certain cancer cells much more selectively than traditional chemotherapy. In the case of PLUVICTO®, this is only possible because the therapy can target a transmembrane protein called PSMA that is most highly expressed in prostate cancer cells. Some normal tissues may also express PSMA, but to a lesser extent, so dosage to healthy organs is a relevant concern that can be managed with appropriate care and attention by experienced nuclear oncology providers. Side effects of RPT can occur, however they are generally much better tolerated compared to other treatments.

PLUVICTO® is paired with PSMA PET/CT imaging before treatment and with follow-up imaging during care, helping clinicians confirm PSMA expression and assess how the dose is distributed to healthy organs. “We know ahead of time where our treatments are going since we’re able to image them,” explains Dr. Ghesani, “and we’re able to do a targeted scan for that particular cancer and know in advance if it expresses what the radiopharmaceutical is designed to find.” In effect, nuclear oncologists can better assess whether the cancer is likely to respond before treatment begins in earnest, a difference that Dr. Ghesani calls “revolutionary.”

Why the 2022 Approval Came After Chemotherapy

The original FDA approval in 2022 came after the VISION trial and applied to patients with PSMA-positive mCRPC who had already received an androgen receptor pathway inhibitor and taxane-based chemotherapy. “Originally, the trials were conducted to see how [PLUVICTO®] would fit in,” explains Dr. Ghesani. At this time there were no other treatment options after patients had chemotherapy, other than additional chemotherapy. This meant that PLUVICTO® had the potential to address an unmet need at the time. For patients who had exhausted most other treatment options, the risk-benefit assessment favored trying this new approach. That being said, many predicted (due to the nature of the treatment) that it would be even more effective earlier, even in those who had not yet received chemotherapy.

The 2025 Update: What Changed and Why It Matters

The 2025 FDA expansion was informed by the PSMAfore trial, which supported use before chemotherapy in PSMA-positive mCRPC (after progression on an ARPI). The newer, pre-chemo approval means that additional patients could qualify for PLUVICTO® treatment at an earlier stage in their cancer journey. Those patients may see a delayed or even reduced need for chemotherapy and its associated side effects.

Another critical aspect of this update is that it maximizes the likelihood that the patient is expressing PSMA, the cell surface protein the drug is designed to find and bind to. As Dr. Ghesani explains, that expression isn’t guaranteed to persist. “In general, data shows that as a patient’s cancer journey continues, they can start to lose PSMA expression,” he notes. “Treating patients before chemotherapy increases the odds that they’ll be showing PSMA expression at that stage.” At the start of the mCRPC journey, roughly 7-8% of patients may already be PSMA-negative, which would make them ineligible for PLUVICTO®, regardless of when it’s offered. But a 2025 study found that docetaxel chemotherapy can reduce PSMA uptake later in a patient’s prostate cancer journey, and particularly in patients who respond well to treatment. This suggested that the window for PSMA-targeted therapy may be most favorable before chemotherapy began, and led the authors of the study to write that the therapy “might have improved efficacy prior to chemotherapy rather than after.” In other words, the earlier a patient can be evaluated and treated, the more likely their cancer is to still have the molecular target PLUVICTO® needs.

Who Now Qualifies for Pre-chemo Treatment with Pluvicto?

To be eligible for PLUVICTO® under the new pre-chemo indication, a patient generally needs to:

• Have metastatic castration-resistant prostate cancer (mCRPC)
• Have progressed on an androgen receptor pathway inhibitor (ARPI)
• Have PSMA-positive disease, confirmed by a PSMA PET/CT scan

PSMA positivity is critical, and even patients with low-grade PSMA positivity may be excluded. Dr. Ghesani was careful to note that not every patient will qualify on that basis. For those who are PSMA-negative, other treatment pathways exist and should be discussed with their care team. Fortunately, only a minority of metastatic prostate cancer is PSMA-negative. It’s worth noting that there are patients who may qualify on paper, but for whom a physician might still recommend a different approach, which is why individualized consultations are so essential to the treatment process.

What Does Treatment Look Like?

The treatment course under the new pre-chemo indication is similar to what patients experienced post-chemo: six doses, spaced approximately six weeks apart. At United Theranostics, the process begins well before the first administration, with an extensive consultation with patients (before any treatments have been administered). During this consultation, United Theranostics nuclear oncology physicians gain an understanding of the patient’s treatment journey, their comorbidities, and other conditions that need to be taken into account, such as their genetics and radiation safety considerations.

After qualifying theranostic pre-treatment planning, patients receive their first treatment and then follow a carefully planned schedule. Dr. Ghesani emphasizes that the team builds this schedule around the patient’s life, rather than around their treatment. “We are mindful that these patients have a life outside of our therapies…so we take into account their personal commitments, their travel plans, etc., because you need to be mindful about the radiation safety,” he explains.

Side Effects: How PLUVICTO® Compares to Chemotherapy

For many patients, one of the most meaningful differences between PLUVICTO® and traditional chemotherapy is the side effect profile. PLUVICTO® typically has a different side-effect profile and does not usually cause hair loss or the same degree of broad immune suppression, though it can still cause clinically important blood-count, kidney, and dry-mouth side effects. The most common side effects typically include mild fatigue, dry mouth, dry eyes, nausea, vomiting, constipation, or diarrhea. That being said, these symptoms are also generally consistent with prostate cancer at a low level, and are transient, lasting typically less than a week in the smaller subset of patients that experience these symptoms at all. Dr. Ghesani has found that patients often become accustomed to these side effects, and it’s not until after they’ve received treatments and the course is reversed at such a rapid level that “they inevitably share with us how amazed they are with the significance of their improvement. They didn’t realize how significant their deterioration had been.”

That quality-of-life improvement is supported by trial data. A published secondary analysis from the VISION study reported that patients receiving PLUVICTO® maintained their quality of life and pain scores significantly longer than patients receiving standard treatment.

Radiopharmaceutical Dosimetry-Guided Treatment: United Theranostics’ Approach

United Theranostics goes beyond providing one standard treatment plan for most patients by offering PLUVICTO® treatment guided by radiopharmaceutical dosimetry. The team uses post-treatment NIST-traceable quantitative SPECT/CT to assess how the radiopharmaceutical is distributed, and to measure absorbed dose, with the goal of maximizing the impact on tumors, while limiting the impact on other organs.

As Dr. Ghesani describes it, this is the natural extension of everything that makes theranostics different:

“At United Theranostics, not only do we begin with a personalized pre-qualification process, but we actually follow up on that by confirming the delivery of these treatments on our SPECT/CT scans. We confirm delivery and quantify how [the treatment] is performing.”

Therapeutic treatment guided by personalized radiopharmaceutical dosimetry remains a particular specialty of United Theranostics Nuclear Oncology Centers of Excellence. United Theranostics’ level of personalization in radiopharmaceutical therapy is rarely available to patients in other outpatient treatment centers, or even at major academic centers. Our patients receive a meaningfully more concierge-level standard of care.

What’s on the Horizon?

The move to pre-chemo eligibility is significant, but it may not be the last evolution. Research is already underway exploring the use of PLUVICTO® in even earlier settings, including hormone-sensitive prostate cancer. Dr. Ghesani is cautiously optimistic about this, but notes that oncologists “need to manage [patients] in a very proactive way so as to minimize side effects and continue to the [highest possible] quality of life for years to come.”