LuPSMA May Fill Gap in Advanced Prostate Cancer After Exhaustion of Standard Treatments

Typical treatment for men with prostate cancer includes androgen deprivation therapy (ADT) and hormone therapy, but eventually, patients progress on these treatments and potentially progress into a more lethal phenotype of the disease for metastatic castration-resistant prostate cancer (mCRPC).

Several agents have been approved for the treatment of men with advanced, late-stage prostate cancer, which include chemotherapy agents, antiandrogen treatments, radiopharmaceuticals, and PARP inhibitors. However, many patients will still go on to progress and will exhaust all standard treatments. 177Lutetium-prostate-specific membrane antigen (LuPSMA) appears to be a potential new treatment option for these patients.

LuPSMA can serve as an option for patients who have previously progressed on all other conventional treatment modalities. The treatment is supported by data that were presented during the 2020 Virtual American Society of Clinical Oncology Virtual Scientific Program. The analysis demonstrated that several factors may be predictors of response to treatment in patients with mCRPC, such as shorter times since diagnosis and their history with chemotherapy treatments, among others.

In an interview with Targeted Oncology, Andrei Gafita, MD, of the Department of Nuclear Medicine at Klinikum Rechts der Isar at the Technical University Munich, discussed the recent findings from the international multicenter retrospective analysis of LuPSMA as treatment of patients with mCRPC, and how these findings and more clinical trials could lead to the approval of this treatment for patients who have exhausted all other standard treatments.

TARGETED ONCOLOGY: Could you first introduce LuPSMA as a treatment option for patients with prostate cancer? Where does it fit into the treatment landscape?

Gafita: Lutetium PSM a treatment is a novel systemic treatment that is currently still under clinical investigation. Multiple retrospective large series, as well as phase 2 evidence, have led to an ongoing phase 3 trial called VISION trial, which is now aiming at drug approval. Men with prostate cancer are initially treated with ADT with hormone treatment, but most of them eventually progress, and they enter in this lateral Phantom type of disease in the mCRPC. In this late, advanced prostate cancer stage, there are several treatments that have been approved like chemotherapy agents such as docetaxel or cabazitaxel, the new generation of antiandrogen treatments such as darolutamide or enzalutamide, the radiopharmaceutical radium223 which is also nuclear medicine treatment, and now the PARP inhibitors. Unfortunately, also in this mCRPC state, most of the patients are progressing, and they exhaust all the standard treatments. Then this is where LuPSMA comes into the landscape in patients who have progressed through all these conventional treatment modalities.

In phase 2 trials, patients have been enrolled who have progressed on taxane-based treatment as well as abiraterone or enzalutamide, so we can claim that LuPSMA is now seen as a third-line treatment in mCRPC.

TARGETED ONCOLOGY: What was the rationale for conducting this particular analysis?

Gafita: No more drugs have been developed since 2003 to predict the survival in prostate cancer, but what we have here in addition to chemotherapy agents or anti-hormones, we have a targeted specific treatment modality. LuPSMA is targeting the PSMA, which is a protein that is expressed also by the normal facet but overexpress a hundred and up to a thousand times higher by the prostate cancer sense. Therefore, we are dealing with a targeted treatment.

On the other side, we have the PSMA-targeted imaging, the PSMA-targeted PET, which has also shown enhanced accuracy in detecting prostate cancer lesion compared to conventional imaging modalities such as CT or MRI. For LuPSMA, all the patients need to be screened with the PSMA-targeted PET imaging to show the presence of PSMA-avid prostate cancer patients. These is eligibility criteria, but for now, they are included if they show the presence of disease but not the degree of the positivity.

In a clinical framework, we were seeing the PSMA PET imaging, we see there's enough uptake and then we just do the treatment. This diagnostic concept or the combination between having an imaging and treatment that is targeting the same target that triggered us that we could use this baseline imaging to predict patient outcome to the treatment and to not only to use this qualitative assessment but also to quantify the images to understand if a higher degree of PSMA expression or higher tumor volume can predict overall survival or progression-free survival (PFS) so the treatment outcome.

The aim is to develop a prognostic model that will predict how the patient will perform to the treatment and also later on in the course of mCRPC.

TARGETED ONCOLOGY: Do you want to elaborate more on these findings?

Gafita: Mainly we included, in this prognostic model, the clinical features or parameters that are included, there are clinically routinely acquired for patients with mCRPC, but in addition, we extensively quantify or extract different features from this PSMA-targeted imaging, and then we put together all these demographics, clinical history, laboratory tests, and combine with the imaging features to just sum up into a predictive and prognostic model to look for the survival. We look very into detail in the PSMA imaging, and we've tracked again the, the tumor signal intensity that should reflect the degree of the PSMA expression in tumor lesions. Then we looked for the tumor volume and also the extent of disease that was assessed according to the PROMISE criteria that have been developed by our collaborators. This is an international multicenter retrospective study that included 6 institutions across the United States of America, Germany, and Australia.

Half of the patients have been treated under compassionate access programs while almost half of them are treated in phase 2 clinical trials. We ended up with 270 eligible patients.

For overall survival, we found that time since the diagnosis of prostate cancer as well as the previous chemotherapy status, so whether the patients had already received chemotherapy or not, then also higher A shorter time since the diagnosis of prostate cancer, as well as the previous chemotherapy status, higher levels of alkaline phosphates at baseline before treatment initiation, lower levels of hemoglobin, lower PSMA expression within the tumor lesions, a higher number of metastasis, more extensive disease, and the presence of liver metastases were all associated with a shorter survival.

We found similar parameters to be predictive for a shorter PSMA PFS, and in addition to that, what is very important in terms of added value for LuPSMA is a new way to qualitatively assess the degree of PSMA expression and namely to compare the degree of tumor PSMA expression with the degree of salivary gland to my expression, the salivary glands PSM expression. We know that that we have PSMA accumulation within several organs that is physiologically and this includes the salivary glands, kidneys, liver, spleen and bladder, so what we found is if a patient has a PSMA expression within the tumor higher compared to salivary gland, he's more likely to have a better PSMA PFS, so better treatment outcome.

TARGETED ONCOLOGY: Are there any next steps planned right now for this research?

Gafita: We would also like to include several other end points, such as the PSMA biochemical response, which is an end point in phase 2 clinical trials. We would also like to eventually apply advanced machine learning techniques to improve the results.

TARGETED ONCOLOGY: What are the key takeaways from this?

Gafita: The key finding of our study is that we showed in a large multicenter setting that several known parameters to be predictive for survival and for treatments in mCPRC also are available for the LuPSMA. And in addition, that PSMA expression within the tumor, according to the baseline PSMA PET, were also predicted for both survival and treatment response.

<< View data from a phase 2 clinical trial of LuPSMA in mCRPC