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Rohan Garje, MD, on First Targeted Radioligand Therapy for mCRPC

<ѻý class="mpt-content-deck">– Panel member of ASCO guideline update offers perspective on novel therapy

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ASCO has issued a based on the FDA approval earlier this year of lutetium Lu 177 vipivotide tetraxetan (Pluvicto), the first targeted therapeutic radioligand for metastatic castration-resistant prostate cancer (mCRPC).

The newly approved therapy delivers targeted beta-particle radiation to cancer cells that express prostate-specific membrane antigen (PSMA). Approval was based on the VISION trial, which showed significant improvements in progression-free survival and overall survival in patients with PSMA-positive mCRPC, the expert panel that developed the recommendations explained.

"The availability of this theranostic option provided a strong signal to update the 2014 guideline with a rapid recommendation for 177Lu-PSMA-617. Complete updates to the mCRPC guidelines are underway," the authors wrote.

They recommended using 177Lu-PSMA-617 intravenously once every 6 weeks for four to six cycles as a treatment option in patients with PSMA PET/CT–positive mCRPC that progressed on one prior line of androgen receptor pathway inhibitor and at least one line of prior chemotherapy.

In addition, the team said, patients should be selected with PSMA PET, and either Ga-68 PSMA-11 or F-18 piflufolastat should be used as radiotracers to determine eligibility.

In the following interview, panel member Rohan Garje, MD, chief of Genitourinary Medical Oncology at the Miami Cancer Institute, offered practical advice on using the therapy and discussed the data that informed the new recommendations.

FDA approval was based on the VISION trial. However, the expert panel reviewed additional clinical trials and observational studies. How did this additional data influence or inform your recommendations?

Garje: VISION was on the only randomized phase III study that evaluated the efficacy of 177Lu-PSMA 617 in patients with mCRPC who were previously treated with an ARPI [androgen receptor pathway inhibitor] and taxane-based chemotherapy. Based on a significant rPFS [radiographic progression-free survival] and OS [overall survival] benefit compared to protocol-permitted standard-of-care therapy, it received FDA approval in March 2022.

Additionally, we also reviewed other published studies that included the clinical trial, which compared the safety and efficacy of 177Lu-PSMA 617 to cabazitaxel in patients with mCRPC who received prior docetaxel.

In this study, 177Lu-PSMA 617 had better PSA [prostate-specific antigen] response rate and PFS; median survival, however, was similar in both arms. Additionally, high PSMA-PET SUV [standard update value]mean of ≥10 (when compared to SUVmean <10) was associated with better PSA response rate.

The serious grade 3 or 4 events were less with 177Lu-PSMA 617 when compared to cabazitaxel, and quality-of-life metrics were also better with 177Lu-PSMA 617.

What practical information or advice to clinicians can you offer for using Lu-PSMA-617?

Garje: Administration of 177Lu-PSMA 617 requires multidisciplinary collaboration and referral to centers with experience in radiopharmaceutical administration. Patients with mCRPC should be selected based on a positive PSMA scan as detected by Ga 68 PSMA-11 or 18F-DCFPyl (piflufolastat). Clinicians should be aware of possible side effects such as dry mouth, fatigue, nausea, myelosuppression, etc., and regularly monitor blood counts and comprehensive metabolic panel.

Ongoing clinical trials are exploring this therapy in earlier-stage disease. Could this therapy be effective in earlier-stage disease or as first-line therapy?

Garje: It's exciting to see multiple clinical trials exploring 177Lu in earlier lines of therapy. For example, (NCT04720157) is exploring the efficacy of 177Lu-PSMA 617 along with standard of care (SOC: ADT + ARPI) when compared to SOC alone in the first-line setting for patients with metastatic hormone-sensitive prostate cancer.

Other studies such as (NCT04689828) and (NCT04647526) are also evaluating 177Lu in earlier lines of mCRPC. In the frontline setting, ADT and ARPIs can enhance the radio-sensitivity of 177Lu PSMA. It would be interesting to see if the early use in the first-line setting would produce durable responses, as the responses noted in refractory mCRPC are not durable.

Also, a word of caution regarding upfront use of 177Lu and potential risks for long-term effects on the salivary glands, including dry mouth, myelosuppression, and renal function.

Are there any other promising targeted therapies in development for patients with prostate cancer?

Garje: Within the realm of radioligand therapeutics, additional agents targeting PSMA such as Actinium 225 (), Thorium-227 (), and Copper-67 () are in clinical trials.

T-cell engaging antibodies that activate cytotoxic T-cells by binding CD3 on T cells, as well as PSMA () or other tumor cell antigens such as STEAP1 (), KLK2 (), and TMEFF2 (), are also in early phases of clinical development. Similarly, multiple early-phase trials are evaluating CAR-T therapy for the treatment of refractory prostate cancer.

Is there anything else you want to make sure oncologists understand about this update or this therapy?

Garje: 177Lu-PSMA 617 is the first novel PSMA-targeting radioligand therapy approved for prostate cancer. This guideline update provides information regarding selecting patients for this therapy.

It is important to note that there are additional treatment options for patients with mCRPC who had prior therapy with ARPI and docetaxel chemotherapy such as cabazitaxel and PARP inhibitors (olaparib, rucaparib) for patients with mutations in DNA repair genes such as BRCA1/2, and pembrolizumab for those with MSI-H [microsatellite instability-high]/TMB [tumor mutational burden] >10 mut/MB.

It is important for practicing physicians to use appropriate treatment based on the patient's clinical status and ability to tolerate a particular therapy.

Read the study here.

Garje reported institutional research funding from Endocyte/Advanced Accelerator Applications, Pfizer, Amgen, Immunomedics, and Xencor.

Primary Source

Journal of Clinical Oncology

Source Reference:

ASCO Publications Corner

ASCO Publications Corner