[Prostate Cancer Commentary Vol. 143 PCa Commentary #143: ANTI-PSMA 177-LUTETIUM RADIOLIGAND THERAPY discusses the mechanism of action of 177Lu therapy, its background and outcome of early studies] (control+click above link to follow or visit https://prostatecancerfree.org/prostate-cancer-news)
The results of the VISION trial, the study on which the FDA based its eagerly awaited approval for Radioligand Therapy (RLT) with Lu177, were published in the New England Journal of Medicine in June 2021: Sartor et. al., “Lutetium-177—PSMA-617 for Metastatic Castration-Resistant Prostate Cancer.” It is worth noting both the eligibility criteria for entrance into this randomized study and the characteristics of the 850 heavily pretreated participants. The forthcoming Novartis Protocol will require the same eligibility qualifications. The VISION trial enlisted men who had prior exposure to androgen suppression (Lupron for example), one additional androgen receptor inhibitor (e.g., Zytiga or Xtandi) and one chemotherapy agent. For men who refused or were unsuited for chemotherapy that requirement was waived. The study compared men treated with Lu-177 RLT plus ADT versus any type of androgen suppression therapy.
Staging required a 68-Ga-PSMA-11 PET/CT and a standard CT, bone scan and MRI. The protocol required having at least one PSMA PET positive metastases up to 5 cm in size. If the CT imaged metastases were not PSMA positive on the accompanying PSMA PET scan that man was excluded from the study.
This exclusion was based on the assumption that this discrepancy indicated that the CT lesion contained some or extensive neuroendocrine transformed cancer. Neuroendocrine cancer does not express PSMA and would not be expected to respond to 177Lu RLT or might require accompanying chemotherapy. 8.7% of men were disqualified on this basis. In the study 91% of men had bone metastases and 50% nodal metastases. 97% had had prior docetaxel and 37% prior cabazitaxel.
For men considering participating in this new Novartis Protocol the VISION trial results provide context. Findings from the VISION trial: image-based progression-free survival for men receiving 177Lu was 8.7 months vs 3.4 months for the control arm; overall survival for 177Lu was 15.3 vs 11.3 months for the standard-of-care arm. The first skeletal event was delayed with RLT to 11.5 months v 6.8 for control. These Kaplan Meier data will be updated as the study matures.
Meyrick et al., Target Oncol. 2021 extracted from their RLT study of 191 men with mCRPC and identified features that best predicted for favorable response and survival: low baseline PSA, predominantly lymph node metastases, and no prior chemotherapy.
In the VISION trial there were few serious adverse effects (grade 3 or worse). Dry mouth and fatigue occurred in > 20% and hematologic suppression in > 30%. In an Australian trial 177Lu RLT had fewer adverse effects than the comparator arm of cabazitaxel chemotherapy.
Lutetium-177 RLT (trade name PLUVICTO) is administered as a short outpatient intravenous infusion. Its 6.7-day half-life requires physical distancing precautions by the recipient for several days. A treatment cycle is 6 weeks.
The Future: What’s Next ? — Answer: Earlier and Earlier Application:
The VISION trial established the substantial efficacy and safety of 177Lu RLT and supports research protocols for its earlier introduction in the sequence of therapy for prostate cancer. The earlier use would introduce it before mutations conferring resistance have developed due to the adaptive pressures of treatment.
177Lu-PSMA-617 offers a welcome and entirely different alternative to the effective, but ultimately limited, hormonal therapies. Early successful application of 177Lu has the potential of delaying the use of hormonal therapy with its inherent adverse effects and ADT’s tendency to accelerated the transition to castration-resistant prostate cancer.
The beta-emissions (high energy electrons) from 177Lu travel a distance of 0.7 and 2.1 mm. They are most effective in smaller lesions. The limited range reduces the toxicity to nearby non-malignant cells such as hematologic precursors in the bone marrow.
Metastatic hormone-sensitive prostate cancer (mHSPC) is currently increasingly diagnosed as a result of the lapse in PSA testing following the 2012 USPSTF Grade D recommendation against PSA screening. However, the now available sensitive PSMA PETCT scans also contribute to finding mHSPC more frequently. In men originally treated for high-risk cancer, 40-70% of men with biochemically recurrence imaged by PSMA PET will be oligometastatic with few metastases. Kroeze et al., European Urology Focus. 2021
A Sampling of Protocols Researching Early 177Lu Applicationp
[“Prostate-Specific Membrane Antigen (PSMA) Theranostics for Treatment of Oligometastatic Prostate Cancer” by Plichta et al., International Journal of Molecular Sciences. Sept. 2021 is a comprehensive review.]
- UpFrontPSMA, an Australian trial, (NCT04343885) “is investigating the use ofdocetaxel in combination with 177Lu-PSMA-617 as compared to docetaxel alone in men with a new diagnosis of high-volume metastatic hormone-naive prostate cancer.” (Plichta et al., International Journal of Molecular Sciences. Sept. 2021), an excellent reference.
- An International Phase III Novartis sponsored trial, NCT04720157, (available at manysites in the US), is investigating the use of 177Lu-PSMA-617 plus ADT compared to hormone suppression alone in men with hormone-sensitive metastatic prostate cancer. Patients randomized to ADT alone may crossover to 177-Lu after progression. [‘617’ designates the antibody that links with the PSMA surface protein.]
Two studies of 177-Lu in metastatic hormone-sensitive oligometastatic cancer:
- A Netherlands study, “Lutetium-177-PSMA-617 in Oligo-metastatic Hormone-Sensitive Prostate Cancer” compares 177Lu RLT therapy (ADT is deferred) to ADT alone in men with recurrent, but hormone-sensitive disease with less than 5 metastatic lesions. (NCT04443062)
- A study of Stereotactic Body Radiation Therapy and 177Lu-PSMA-617 in men with mHSPC, NCT05079698, (Memorial Sloan Kettering Cancer Center). Treatment: two cycles of 177Lu-PSMA-617 followed by stereotactic body radiation therapy to 1 – 3 metastatic lesions in men post-surgery or radiation treatment to the primary.
FDA approval of Novartis’s Pluvicto for metastatic castration-resistant prostate cancer ushers in a promising new era in prostate cancer treatment. New research is probing its earlier application in the treatment sequence.