N Engl J Med 2021 Jun 23
Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer.
Abstract
Background
Metastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (177Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.
Methods
We conducted an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor-pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)-labeled PSMA-11 positron-emission tomographic-computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment.
Results
From June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. 177Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001). All the key secondary end points significantly favored 177Lu-PSMA-617. The incidence of adverse events of grade 3 or above was higher with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected.
Conclusions
Radioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer. (Funded by Endocyte, a Novartis company; VISION ClinicalTrials.gov number, NCT03511664.).
Related Questions
Does the possibility of future Lu-177–PSMA therapy change your current threshold to offer earlier metastasis-directed RT in oligometastatic prostate cancer?
There is a lot of excellent research being done on the efficacy and tolerance of combined Lu-177-PSMA therapy and EBRT. So far, the combination is well tolerated, and there is some data that sequencing the two to allow EBRT to treat the more “Pluvicto-resistant” lesions may help with efficacy.The qu...
Do you modify dosing and monitoring of Lu-177–PSMA therapy for patients with prior large-field RT involving substantial active marrow compared with patients who only had focal bone SBRT?
No, we do not modify dosing and monitoring of PSMA therapy with prior large-field RT. In the VISION trial, the vast majority of patients were heavily pre-treated, presumably many with pelvic radiation for definitive treatment or treatment for bCR prior to metastasis. Assuming that the patient had ap...
For patients starting Pluvicto, do you have patients stop their ARPI?
While the VISION trial allowed for concomitant use, it was only about half (53%) in the Lu-177-PSMA arm, and 2/3 (68%) of those on the standard of care arm - Garje et al., PMID 36693228. And the PSMAfore trial did not, as noted above by @Dr. First LastThe bigger question is, will you continue the AR...
How do you decide between radioligand therapy or cytotoxic chemotherapy in patients with metastatic castration-resistant prostate cancer with prior ARPI exposure who have cancer-related anemia?
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Are there any contraindications to Pluvicto therapy you personally use, given that there are none directly provided by the manufacturer?
In this situation, it is helpful to review the eligibility and exclusion criteria from the VISION protocol directly. These can be found at NCT03511664 (Sartor et al., PMID 34161051). Many of these patients have been heavily pretreated, including prior taxane therapy, so my main concern is that they ...
What criteria are you using for retreatment with Pluvicto (Lu-177) in those who maintain a good performance status and appropriate lab work?
Mainly, whether or not they've exhausted standard options. At the time I'm answering this, Pluvicto is approved for castration-resistant metastatic disease, either pre- or post-taxane chemotherapy. If they have not had chemo, I usually recommend it. If they have, I get their medical oncologist to we...
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Lung Cancer New first line therapy for advanced EGFR Exon 20 NSCLC patients: The PAPILLION trial [Zhou et al., PMID 37870976] was a Phase 3 clinical trial among patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with documented epidermal growth factor receptor (EGFR) ex...
How do you sequence Ra-223 and Lu-177 in patients with mCRPC with predominantly bony disease?
The RALU study (Rahbar et al., PMID 36302656) really is quite a small 49-patient cohort study looking at the one-way question of the safety of PSMA-Lu177 in carefully selected patients who had adequate marrow function after both an ARSI, taxane chemo, and radium-223. While these selected patients to...
Is it safe to administer Lu-177 therapies in patients with epidural disease in the spinal canal?
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How does the presence of PSMA negative lesions in a patient with mCRPC affect your decision to treat with Lutetium (177Lu) vipivotide tetraxetan?
The tl;dr answer: If the patient met VISION criteria for exclusion based on PSMA-negative disease burden, then yes, I would most likely not recommend Pluvicto and would prefer alternative systemic options. Consider cabazitaxel if the patient has already seen docetaxel. Also, ensure the patient has b...
Can you give Pluvicto with concurrent palliative EBRT?
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How do you manage dry eye related to Pluvicto Lu-177?
This is a real but uncommon side effect of Pluvicto therapy. Per VISION, it will happen in maybe 3% of patients but almost never high grade. Interestingly, the absorbed dose for the lacrimal glands is 2.1 Gy/Gbq - which over 6 cycles full dose at 7.4 GBq/200 mCi per cycle means 92 Gy. There was a me...
Do you continue androgen receptor pathway inhibitors in patients receiving Lu177-PSMA for metastatic prostate cancer?
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Do you account for prior EBRT when treating with 177Lu-PSMA-617?
No, we do not account for it. In the future, with a better understanding and implementation of Dosimetry, it may be important, particularly as LuPSMA moves into earlier lines of care.Patients receiving this therapy are heavily pretreated often with RT in the VISION study. We use palliative radiation...
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In a patient with metastatic prostate cancer on abiraterone planning to start Radium-223, what is the minimum interval between the last dose of abiraterone and the first dose of Radium?
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