What Comes After Pluvicto? A New and Distinct Prostate Cancer Patient Subpopulation Is Taking Shape

Treatment decisions are more than selecting which therapy, but also when to use it. This sequencing of therapies in advanced prostate cancer has been in constant evolution over the past 15 years. Androgen pathway inhibition in the form of androgen deprivation therapy (ADT) has traditionally been initiated in early recurrent disease, and chemotherapy in later overtly metastatic disease, specifically metastatic castration resistant prostate cancer (mCRPC).  

With the introduction of androgen receptor pathway inhibitors (ARPIs) over a decade ago, initially used in mCRPC, these agents are now more commonly initiated earlier in castration sensitive disease (known as CSPC) and second and third line ARPIs are used in mCRPC. Chemotherapy has recently reemerged in certain very aggressive clinical scenarios in CSPC as well. With that said, there remains a strong sentiment by patients and doctors to delay, if not avoid, chemotherapy because of its adverse event profiles and impact on quality of life.  

With the recent arrival of PSMA-targeted radioligand therapy, sequencing continues to evolve. With the approval and growing use of therapies like Pluvicto, clinicians have a new and meaningful therapeutic option for patients with mCRPC.

But in practice, another question is beginning to surface: What happens after PSMA-targeted therapy?

Several issues are becoming increasingly apparent. First, most patients do not derive durable benefit from Lu-177 PSMA-targeted therapy. While many respond (perhaps less than 50%), most progress, some relatively quickly, consistent with a pattern seen in oncology whereby tumors are inherently resistant  (de novo) or evolve in response to therapeutic pressure to become resistant.

Second, the field has largely focused on increasing access to Lu-177 PSMA-targeted therapy and on moving it earlier in the treatment sequence. While identifying the utility of Lu-177 PSMA-targeted therapy in earlier lines of prostate cancer is important, considerably less attention has been paid to the therapeutic options that follow after Lu-177 PSMA-targeted therapy. 

Lastly, once patients have received Lu-177 PSMA-targeted therapy, the therapeutic path forward is not well defined. There is no established standard of care for this group. To wit, the most prominent sources for treatment guidelines (e.g., ASCO, ESMO, NCCN) have not recommended an approach. Consequently, treatment decisions often rely on physician judgment rather than clear evidence. 

From a clinical perspective, Lu-177 PSMA-targeted therapy has become part of the treatment landscape but is not curative. It is one phase of a continuum, and we need to understand what comes next.

Defining a new patient population

This emerging group, informally referred to as the those in the “post-Pluvicto” setting, is not a single, homogeneous population. It includes patients who were marginal candidates based on borderline PSMA expression on qualifying PET scans for PSMA-targeted approaches in the first place, those who have progressed despite Lu-177 PSMA-targeted therapy, patients who derived initial benefit but eventually whose tumors became resistant, and finally patients who remain sensitive to this treatment. 

What unites them is not a specific biomarker (for example PSMA expression persists in most patients despite resistance), but a shared clinical context: they have moved through some of the most advanced therapies currently available and still require additional options.

Because of the inherent heterogeneity of the post Lu-177 PSMA-targeted therapy population, this group is not yet well-characterized in the published literature but is increasingly visible in clinical practice. As PSMA-targeted therapy becomes more widely used and moves earlier in the treatment sequence, the number of patients in this post-treatment phase will only grow. For clinicians, researchers, and those evaluating from where the next meaningful advances in this space will come, understanding this population is becoming increasingly important.As stated, PSMA continues to be expressed on the surface of prostate cancer cells even after prior PSMA-targeted therapy — a finding that has meaningful implications. It suggests that the target itself has not disappeared and that new strategies for engaging it may be used. This creates a genuine opportunity: the biology has left the door open for further targeting of PSMA, but the existing therapeutic approaches may no longer be sufficient on their own.

What we still don’t know

We do not yet have a clear understanding of the anticipated survival duration of such patients, let alone how they respond to subsequent therapies. Key questions remain open: How does prior PSMA-targeted exposure affect tumor biology and target availability? What levels of PSMA expression persist, and are they sufficient to support re-targeting? How do cumulative toxicities — particularly to renal, salivary and lacrimal gland, and bone marrow function — constrain what can safely follow? The last point is particularly germane to Lu-177 PSMA-targeted therapy that utilizes small-molecule PSMA targeting moieties.  These readily expose kidney and salivary glands to radiation as they are filtered through the kidneys and enter the salivary glands, both sites of significant physiologic PSMA expression.

In the post-ARPI, post-taxane, post-Lu-177 PSMA-targeted population, except for overall survival, there is no consensus on what if any intermediate clinical benchmarks define meaningful benefit in this population. Biochemical response and, perhaps more importantly, durability of response, safety, tolerability, and ease of drug administration all carry greater weight in a population where treatment burden is already high. Establishing these benchmarks is not a secondary concern — it is a precondition for evaluating whether new therapeutic approaches are promising and should continue clinical development.

Novel Approaches to Re-Targeting

Given that PSMA expression persists, several investigational strategies are being explored on how to engage the target differently rather than abandoning it. The two driving variables to modify are the type of radiation delivered, often called the payload, and the mechanism of targeting.

With respect to the payload, although Rad-223 was approved for advanced prostate cancer and is an alpha emitter, it targets the bone microenvironment rather than the prostate cancer itself.  Pluvicto uses Lu-177 which is a beta-emitting isotope. Alpha-emitting isotopes, by contrast, deliver higher-energy radiation over a shorter range — a characteristic that may be particularly relevant in the post-treatment setting, where minimizing cumulative toxicity while maintaining tumor effect becomes a central consideration.  Actinium-225, which has a convenient half-life of 9.9 days, is the most commonly used alpha emitting isotope.  Initial concerns about supply limitations have disappeared given the advancement of accelerator accelerator-derived Actinium-225.  Concerns about daughter isotopes have been dismissed based on dosimetry data.  Lead-212 is another isotope in consideration.  Its use however is limited because of its short half-life (10.6 hours) requiring overnight shipping restricting its use to locations close to the production facility.  In addition, its daughters emit high energy gamma radiation requiring heavy shielding during shipping and handling.

For the mechanism of targeting, active research is focused on the carrier molecules. Given that Lu-177-based PSMA therapy targets the catalytic site of PSMA, targeting other moieties on the PSMA molecule may be advantageous given that it was previously targeted.  For example, using an antibody approach which targets the apical region of the molecule may serve as a unique approach.  This may help circumvent mechanisms that limit the effectiveness of prior therapies. Their pharmacokinetic profiles and tissue distribution also differ from small molecules, potentially minimizing exposure to and accumulation in normal tissues, thereby improving tolerability.

There are several approaches under investigation, and no single strategy has yet shown superiority in this setting. However, it is clear that the field is moving toward differentiated mechanisms that can re-engage viable targets in patients who have already received highly targeted prior therapy.  This is a common theme in cancer therapies.

Implications for the Field

Recognizing the “post-Pluvicto” setting as a distinct clinical and research priority has several practical implications.

For clinical trial design, it means more explicitly characterizing patients who have received prior Lu-177 PSMA-targeted therapy. It also potentially means developing unique endpoints appropriate to this population.

For drug development, it means that differentiation will matter. Therapies that can offer a meaningful mechanism distinct from existing Lu-177 PSMA-targeted approaches — whether through isotope selection, delivery platform, binding strategy, or combination potential — will be better positioned to demonstrate value in this setting.

For the broader field, it means paying closer attention to a patient population that is growing in size, underserved by current options, and increasingly visible to clinicians navigating real-world treatment decisions. This mindset helps to deliver to patients the promise of precision therapy.

The success of Lu-177 PSMA-targeted therapy represents a genuine and meaningful advance for patients with advanced prostate cancer. At the same time, it has created a new set of clinical questions that the field is only beginning to address. The task now is to better define this emerging phase of care, characterize the patient population more precisely, establish appropriate clinical benchmarks, and develop approaches that can extend meaningful benefit to patients who have already progressed through the most advanced therapies available.

Photo: rudall30, Getty Images

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