[ 177 Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study

Hofman, Michael S; Violet, John; Hicks, Rodney J.; Ferdinandus, Justin; Thang, Sue Ping; Akhurst, Tim; Iravani, Amir; Kong, Grace; Kumar, Aravind Ravi; Murphy, Declan; Eu, Peter; Jackson, Price; Scalzo, Mark; Williams, Scott; Sandhu, Shahneen

doi:10.1016/s1470-2045(18)30198-0

Cited by 892 publications

(951 citation statements)

References 28 publications

Supporting

Mentioning

815

Contrasting

Unclassified

Order By: Relevance

“…More recently, results of the first prospective study of 177 Lu‐PSMA‐617 were published . Australian investigators enrolled 43 men with mCRPC and treated 30 (excluding 7 [16%] due to imaging results).…”

Section: Discussionmentioning

confidence: 99%

Phase 1/2 study of fractionated dose lutetium‐177–labeled anti–prostate‐specific membrane antigen monoclonal antibody J591 (¹⁷⁷Lu‐J591) for metastatic castration‐resistant prostate cancer

Tagawa

Vallabhajosula

Christos

et al. 2019

Cancer

106

View full text Add to dashboard Cite

Background Prostate cancer is radiosensitive. Prostate‐specific membrane antigen (PSMA) is selectively overexpressed on advanced, castration‐resistant tumors. Lutetium‐177–labeled anti‐PSMA monoclonal antibody J591 (177Lu‐J591) targets prostate cancer with efficacy and dose‐response/toxicity data when delivered as a single dose. Dose fractionation may allow higher doses to be administered safely. Method Men with metastatic castration‐resistant prostate cancer refractory to or refusing standard treatment options with normal neutrophil and platelet counts were enrolled in initial phase 1b dose‐escalation cohorts followed by phase 2a cohorts treated at recommended phase 2 doses (RP2Ds) comprising 2 fractionated doses of 177Lu‐J591 2 weeks apart. 177Lu‐J591 imaging was performed after treatment, but no selection for PSMA expression was performed before enrollment. Phase 2 patients had circulating tumor cell (CTC) counts assessed before and after treatment. Results Forty‐nine men received fractionated doses of 177Lu‐J591 ranging from 20 to 45 mCi/m2 ×2 two weeks apart. The dose‐limiting toxicity in phase 1 was neutropenia. The RP2Ds were 40 mCi/m2 and 45 mCi/m2 ×2. At the highest RP2D (45 mCi/m2 ×2), 35.3% of patients had reversible grade 4 neutropenia, and 58.8% of patients had thrombocytopenia. This dose showed a greater decrease in prostate‐specific antigen (PSA) levels and longer survival (87.5% with any PSA decrease, 58.8% with >30% decrease, 29.4% with >50% decrease; median survival, 42.3 months [95% confidence interval, 19.9‐64.7]). Fourteen of 17 (82%) patients with detectable CTCs experienced a decrease in CTC count. Overall, 79.6% of patients had positive PSMA imaging; those with less intense PSMA imaging tended to have poorer responses. Conclusion Fractionated administration of 177Lu‐J591 allowed higher cumulative radiation dosing. The frequency and depth of PSA decrease, overall survival, and toxicity (dose‐limiting myelosuppression) increased with higher doses.

show abstract

Section: Discussionmentioning

confidence: 99%

Phase 1/2 study of fractionated dose lutetium‐177–labeled anti–prostate‐specific membrane antigen monoclonal antibody J591 (¹⁷⁷Lu‐J591) for metastatic castration‐resistant prostate cancer

Tagawa

Vallabhajosula

Christos

et al. 2019

Cancer

106

View full text Add to dashboard Cite

show abstract

“…In addition, PSMA‐based therapy has been investigated as a treatment option for patients with advanced castration‐resistant prostate cancer (CRPC). Several pilot studies using 177 Lu‐PSMA‐617 radioligand therapy showed a relevant antitumor activity and promising response rates in patients with CRPC . Prospective randomized clinical trials with long‐term follow‐up are awaited to confirm the clinical utility of the novel treatment option.…”

Section: Introductionmentioning

confidence: 99%

Concentration‐dependent effects of dutasteride on prostate‐specific membrane antigen (PSMA) expression and uptake of ¹⁷⁷Lu‐PSMA‐617 in LNCaP cells

et al. 2019

View full text Add to dashboard Cite

Background Prostate‐specific membrane antigen (PSMA)‐based imaging and therapy are increasingly used in the management of prostate cancer. However, low PSMA surface expression in certain patients is a limitation for PSMA‐based technologies. We have previously shown that high doses of dutasteride, a 5α‐reductase inhibitor generally used for the treatment of benign prostatic enlargement, increase the PSMA expression in vitro. We now further analyzed the concentration‐ and time‐dependent effects of dutasteride in LNCaP cells. Methods Androgen receptor (AR) expressing prostate cancer cells (LNCaP) were treated for 7 to 14 days with vehicle control (0.1% dimethyl sulfoxide) or different concentrations of dutasteride (0.25 , 0.5 , 1 , and 5 μM). In addition to cell proliferation, PSMA surface expression was assessed using flow cytometry (FACS) and immunocytochemistry. Total PSMA and AR expression was analyzed by capillary western immunoassay (WES). In addition, tumor cell uptake and internalization assays of 177Lu‐PSMA‐617 were performed. Results Dutasteride treatment resulted in a significant upregulation of PSMA surface expression compared to vehicle control after 7 days in all tested concentrations. After 14 days a further, concentration‐dependent increase of PSMA surface expression was detectable. Total PSMA protein expression significantly increased after treatment of cells with high concentrations of dutasteride using 5 μM for 7 or 14 days. However, when lower concentrations were used total PSMA expression was not significantly altered compared to vehicle control. Further testing revealed a dose‐dependent increase in uptake and internalization of 177Lu‐PSMA‐617 after 7 and 14 days. Though, a significantly increased uptake was only observed using a 5 μM dutasteride concentration for 7 days as well as 1 and 5 μM for 14 days. Conclusion Our investigations revealed a concentration‐ and time‐dependent effect of dutasteride on PSMA expression and uptake of 177Lu‐PSMA‐617 in LNCaP cells. A short‐term treatment of patients with high doses of dutasteride might increase the detection rate of PSMA‐based imaging and increase the effect of 177Lu‐PSMA‐617 therapy via upregulation of PSMA expression.

show abstract

“…However, the aforementioned prospective study, describing 177 Lu-PSMA treatment in 30 patients, reported on one case in which base of skull disease caused oculomotor nerve disorder 2 . 177 Lu-PSMA-617 therapy in this patient was continued.…”

Section: Discussionmentioning

confidence: 99%

“…Since its introduction in German institutions several years ago, safety of 177 Lu-PSMA-617 therapy has only been established in one prospective study in which 177 Lu-PSMA-617 therapy was found to be well tolerated with low toxic effects 2. This report describes a case in which a potential therapy-related adverse event occurred.…”

Section: Introductionmentioning

confidence: 94%

Visual deficit possibly caused by lutetium-177 PSMA treatment

Kalmthout¹,

Stam

Gans

et al. 2018

BMJ Case Reports

View full text Add to dashboard Cite

This report describes a case of a 54-year-old man who underwent lutetium-177-PSMA therapy in the setting of metastatic castration-resistant prostate cancer (mCRPC) in the University Medical Center Utrecht. Following administration of the second cycle, patient presented with a slowly impairing, bilateral visual loss. This clinical presentation was most likely the result of the high intracranial pressure due to impediment of cerebrospinal fluid circulation, possibly related to obstructive dural thickness, being either caused by dural and/or leptomeningeal metastases of advanced mCRPC or by local radiation effects following lutetium-177-PSMA therapy. Describing this case, we aim to add to the discussion on 177Lu-PSMA safety, in which prospective research will ultimately offer definite answers.

show abstract

[ 177 Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study

Cited by 892 publications

References 28 publications

Phase 1/2 study of fractionated dose lutetium‐177–labeled anti–prostate‐specific membrane antigen monoclonal antibody J591 (¹⁷⁷Lu‐J591) for metastatic castration‐resistant prostate cancer

Phase 1/2 study of fractionated dose lutetium‐177–labeled anti–prostate‐specific membrane antigen monoclonal antibody J591 (¹⁷⁷Lu‐J591) for metastatic castration‐resistant prostate cancer

Concentration‐dependent effects of dutasteride on prostate‐specific membrane antigen (PSMA) expression and uptake of ¹⁷⁷Lu‐PSMA‐617 in LNCaP cells

Visual deficit possibly caused by lutetium-177 PSMA treatment

Contact Info

Product

Resources

About

[ 177 Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study

Cited by 892 publications

References 28 publications

Phase 1/2 study of fractionated dose lutetium‐177–labeled anti–prostate‐specific membrane antigen monoclonal antibody J591 (177Lu‐J591) for metastatic castration‐resistant prostate cancer

Phase 1/2 study of fractionated dose lutetium‐177–labeled anti–prostate‐specific membrane antigen monoclonal antibody J591 (177Lu‐J591) for metastatic castration‐resistant prostate cancer

Concentration‐dependent effects of dutasteride on prostate‐specific membrane antigen (PSMA) expression and uptake of 177Lu‐PSMA‐617 in LNCaP cells

Visual deficit possibly caused by lutetium-177 PSMA treatment

Contact Info

Product

Resources

About

Phase 1/2 study of fractionated dose lutetium‐177–labeled anti–prostate‐specific membrane antigen monoclonal antibody J591 (¹⁷⁷Lu‐J591) for metastatic castration‐resistant prostate cancer

Phase 1/2 study of fractionated dose lutetium‐177–labeled anti–prostate‐specific membrane antigen monoclonal antibody J591 (¹⁷⁷Lu‐J591) for metastatic castration‐resistant prostate cancer

Concentration‐dependent effects of dutasteride on prostate‐specific membrane antigen (PSMA) expression and uptake of ¹⁷⁷Lu‐PSMA‐617 in LNCaP cells