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.
Photo: rudall30, Getty Images
Philip Kantoff, MD, is a globally recognized leader in prostate cancer research and treatment. He serves as Co-founder and CEO of Convergent Therapeutics and previously held leadership roles at Dana-Farber Cancer Institute, where he directed the Lank Center for Genitourinary Oncology and was Chief of Solid Tumor Oncology. He later served as Chair of Medicine at Memorial Sloan Kettering Cancer Center. Dr. Kantoff has led multiple pivotal clinical trials that have shaped the standard of care in prostate cancer, including work spanning androgen signaling inhibitors, immunotherapy, and radiopharmaceuticals. His research has focused on the biology and clinical management of advanced prostate cancer, with particular emphasis on treatment sequencing and emerging therapeutic modalities.
Richard Messmann, MD is a medical oncologist and clinical research physician with over 30 years of drug development experience, focused on radiotherapeutics, immuno-therapeutics, cytotoxic conjugates, and small molecule cell signal transduction inhibitors. After completing a medical oncology fellowship at the National Cancer Institute, he served as deputy associate director of the NIH/NCI’s Developmental Therapeutics Program (DTP). During and after Novartis’s 2018 acquisition of Endocyte, Inc. he led the clinical team responsible for the global development and registration of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) and gallium Ga 68 gozetotide (Locametz).
Jones T. Nauseef, MD PhD is a medical oncologist and physician-scientist who has focused his career on advanced prostate cancers, with emphasis on patient care, drug development, radiopharmaceuticals, and genomics. He holds a PhD in Molecular Physiology and Biophysics. He serves currently as the Executive Medical Director for Convergent Therapeutics, Inc. and holds a courtesy appointment as Assistant Professor of Medicine at Weill Cornell Medicine.
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