Phase I/II study of fractionated dose lutetium-177 labeled anti-prostate-specific membrane antigen monoclonal antibody J591 (¹⁷⁷Lu-J591) for metastatic castration-resistant prostate cancer

Abstract

Background

Prostate cancer is radiosensitive. Prostate-specific membrane antigen (PSMA) is selectively over-expressed on advanced, castration-resistant tumors. 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.

Patients and Methods

Men with metastatic castration-resistant prostate cancer (mCRPC) refractory to or refusing standard treatment options with normal neutrophil and platelet counts were enrolled in initial phase Ib dose-escalation cohorts followed by phase IIa cohorts treated at recommended phase II doses (RP2D’s) of two fractionated doses of ¹⁷⁷Lu-J591 2 weeks apart. ¹⁷⁷Lu-J591 imaging was performed after treatment, but no selection for PSMA expression was performed prior to enrollment. Phase II had circulating tumor cell (CTC) counts assessed before/after treatment.

Results

Forty nine men received fractionated doses of ¹⁷⁷Lu-J591 ranging from 20 – 45 mCi/m² ×2. Dose-limiting toxicity in phase I was neutropenia. 40 mCi/m² and 45 mCi/m² ×2 were RP2D’s. At highest RP2D (45 mCi/m² ×2), reversible grade 4 neutropenia in 35.3% and thrombocytopenia in 58.8%. Dose-response was observed with more PSA declines and longer survival (87.5% with any PSA decline, 58.8% >30% decline, 29.4% >50% decline; median survival 42.3 months, 95% CI 19.9–64.7). Fourteen of 17 (82%) with detectable CTC counts declined. 79.6% had positive PSMA imaging; those with less intense PSMA imaging tended to have poorer responses.

Conclusions

Fractionated administration of ¹⁷⁷Lu-J591 allowed higher cumulative radiation dosing. The frequency and depth of PSA declines, overall survival and toxicity (dose-limiting myelosuppression) increased with higher dose.

Precis:

Administration of 177Lu-J591 with dose-fractionation allowed higher cumulative radioactivity dosing. The frequency and depth of PSA decline, overall survival, and toxicity (dose-limiting myelosuppression) increased with higher dose.

INTRODUCTION

Prostate cancer (PC) is radiosensitive and different forms of radiation have been validated including bone-targeting radioisotope therapy.^1–3 However, unsealed radiation sources (⁸⁹Sr, ¹⁵³Sm, ²²³Ra) target sites of increased bone metabolism rather than directly targeting tumor. Consequently, the anti-tumor effect derives from indirectly targeting only bone metastases; they have no effect on soft tissue or visceral metastases. As such, a method of targeting radiation-emitting particles directly to tumor cells in bone and soft tissue offers potential advantages.

Prostate-specific membrane antigen (PSMA) is an ideal PC target because: 1) its expression is highly specific, 2) it is expressed by approximately 90% of PCs and 3) we have shown that PSMA functions as an internalizing cell surface receptor.^4,5 We have previously demonstrated that the anti-PSMA monoclonal antibody (mAb) J591 can be successfully radiolabeled and delivered in a single dose with efficacy in patients with mCRPC, but with dose-limiting myelosuppression.^6–11

The degree of anti-tumor response following the administration of targeted radionuclides depends on several variables, especially total (cumulative) radiation dose to the tumor, dose-rate, and tumor radiosensitivity.¹² Bone marrow is the dose-limiting organ in radioimmunotherapy (RIT).^12,13 Dose-fractionation is a practical strategy to decrease the dose to bone marrow while increasing the cumulative radiation dose to the tumor at an optimal dose-rate.^14–16 Here we report safety and efficacy data for a phase Ib/IIa dose-escalation study of fractionated dose ¹⁷⁷Lu-J591 in patients with metastatic CRPC.

PATIENTS AND METHODS

Adults with progressive metastatic CRPC were eligible. Any number of previous regimens was allowed except systemic beta-emitting therapy. Additional entry criteria included ECOG performance status 0 – 2, absolute neutrophil count ≥ 2000/mm³, platelet count ≥150,000/mm³, serum bilirubin ≤1.5x upper limit of normal (ULN), AST ≤ 2x ULN, and serum creatinine ≤ 2.5 mg/dL. This registered study (NCT00538668) was approved by the Weill Cornell Institutional Review Board and the Human Research Protection Office of the U.S. Army Medical Research and Material Command and monitored by the Weill Cornell Medicine Data Safety Monitoring Board. All subjects provided written informed consent.

Treatment:

Preparation and quality control of ¹⁷⁷Lu-J591 was as previously described (details in Supplemental Materials).^9,11 Subjects received 2 doses of ¹⁷⁷Lu-J591 two weeks apart without pre-medication (dose levels in Supplemental Table 1). When dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) without growth factor were determined¹⁷ we simultaneously observed a dose-response relationship in the phase II single-dose study¹¹ and lack of dose-limiting thrombocytopenia with fractionated dosing. Phase II subjects were then enrolled in the recommend phase II dose (RP2D) cohorts in staged design.

Complete blood counts (CBC) were monitored at least weekly until 8 weeks. Filgrastim/pegfilgrastim (but not sargramostim) was allowed in phase II. Chemistry and PSA were monitored at least every 4 weeks. Circulating tumor cell (CTC) count was assessed (CellSearch) at baseline and at 4–6 weeks in phase II.

No patient selection based on PSMA expression was performed. Planar gamma camera imaging was obtained following ¹⁷⁷Lu-J591 infusion. Radiolabeled J591 images were compared to baseline bone scintigraphy and cross-sectional imaging; semi-quantitative PSMA expression analysis was performed with a visual score (VS) as previously published.¹¹ Briefly, VS was performed by two independent radiologists and scored as follows: 0 (no uptake), 1 (weakly positive), 2 (definitely positive), 3 (equal intensity to liver), 4 (greater uptake than liver).

Statistical Plan:

The primary endpoint of the phase I portion was determination of DLT and RP2D. A modified 3+3 dose-escalation design was employed. DLT was defined as previously published [supplemental material].^9,11 As above, following completion of the phase I portion of the study, an amendment was approved to enroll 2 cohorts in phase II. Secondary endpoints included proportion with PSA decline, overall survival, and treatment emergent adverse events by CTCAE v4.

Phase II utilized Simons two-stage minimax design, assuming 10% level of significance and 80% power. If 1 or fewer of the first 9 did not experience > 30% decline in PSA, enrollment would be terminated. If ≥ 2 of the first 9 evaluable had >30% PSA decline, additional accrual proceeded to the target sample size of 16. The new regimen is worthy of further testing if ≥ 5 of 16 patients had > 30% PSA decline, yielding a 0.80 probability of a positive result if the true 30% PSA decline proportion is ≥40% and a 0.90 probability of a negative result if the true 30% PSA decline proportion is <15%.

Kaplan-Meier survival analysis was used to estimate overall survival (OS). Descriptive statistics were performed to characterize the study sample. Fisher’s exact test was used to compare PSA decline response proportions between dose cohorts and between low (0–1) and high (2–4) PSMA visual score (VS). The log-rank test was employed to compare OS between dose cohorts. P-values are two-sided with statistical significance evaluated at the 0.05 alpha level. Analyses were performed in SAS Version 9.4 (SAS Institute) and STATA Version 15.0 (StataCorp).

RESULTS

In the phase I dose-escalation phase, 28 subjects were treated between August, 2007 and April, 2010.¹⁷ An additional 21 were treated between June, 2010 and August, 2014 in phase II cohorts. Baseline demographics are in Table 1. Phase I patients received between 20 – 45 mCi/m² (0.74 – 1.67 GBq/m²) per dose. No DLT occurred in cohorts 1–5 [up to 40 mCi/m² (1.48 GBq/m²) x2] with one subject withdrawing from treatment after only 1 dose with grade 2 infusion reaction (complete AEs listed in Table 2 and described below). In cohort 6 [45 mCi/m² (1.67 GBq/m²) x2], 2 subjects experienced grade 4 neutropenia lasting > 7 days (without fever). As described in Methods, the 40 and 45 mCi/m² ×2 cohorts were declared RP2D levels (with allowance for growth factor in phase II) and expanded, with both cohorts meeting criteria to move forward to stage 2 (16 and 17 subjects at each dose level).

Table 1:

Baseline Characteristics (N=49)

Age, years
Median	72
Range	52–93
Gleason Sum
6	5 (10.2%)
7	15 (30.6%)
8	11 (22.4%)
9	18 (36.7%)
PSA (ng/mL)
Median	44.9
Range	1.9–766.5
Sites of Metastases
Bone	42 (85.7%)
Lung	13 (26.5%)
Liver	6 (12.2%)
Lymph Node	29 (59.2%)
Other	1 (2.0%)
ECOG Performance Status
0	7 (14.3%)
1	38 (72.6%)
2	4 (8.2%)
LDH
Median	192
Range	99 – 625
Hemoglobin
Median	12.7
Range	10 – 16.3
Alkaline Phosphatase
Median	79
Range	22 – 490
CALGB Prognostic Group
High	28 (57.1%)
Intermediate	17 (34.7)
Low	4 (8.2%)
Previous Systemic Therapies
Docetaxel	18 (36.7%)
Abiraterone/Enzalutamide	9 (18.4%)
Radium-223	1 (2.0%)
Sipuleucel-T	5 (10.2%)
Radiation	34 (69.4%)

Abbreviations: PSA = prostate specific antigen; LDH = lactate dehydrogenase; ECOG = Eastern Cancer Cooperative Group; CALGB = Cancer and Leukemia Group B

Table 2:

Treatment emergent toxicities

CTCAE Toxicity	Grade 1–2	Grade 3	Grade 4	Total
Non-Hematologic
Fatigue	23 (46.9%)			23 (46.9%)
Hypersensitivity (aka Infusion Reaction)	18 (36.7%)			18 (36.7%)
Weight Loss	17 (34.7%)	1 (2%)		18 (36.7%)
Nausea	13 (26.5%)			13 (26.5%)
Pain - Localized	9 (18.3%)	4 (8.2%)		13 (26.5%)
AST (SGOT)	10 (20.4%)			10 (20.4%)
Dyspnea	9 (18.4%)			9 (18.4%)
Anorexia	8 (16.3%)			8 (16.3%)
Edema: limb	7 (14.3%)			7 (14.3%)
Constipation	6 (12.2%)			6 (12.2%)
Diarrhea	6 (12.2%)			6 (12.2%)
Insomnia	6 (12.2%)			6 (12.2%)
Urinary frequency	6 (12.2%)			6 (12.2%)
Cough	5 (10.2%)			5 (10.2%)
Pain - Joint	4 (8.2%)	1 (2%)		5 (10.2%)
Epistaxis	4 (8.2%)			4 (8.2%)
Anxiety	3 (6.1%)			3 (6.1%)
Depression	3 (6.1%)			3 (6.1%)
Dizziness	3 (6.1%)			3 (6.1%)
ALT (SGPT)	2 (4.1%)			2 (4.1%)
Confusion	2 (4.1%)			2 (4.1%)
Creatinine	2 (4%)			2 (4%)
Headache	2 (4.1%)			2 (4.1%)
Memory loss	2 (4.1%)			2 (4.1%)
Pain - Abdomen NOS	2 (4.1%)			2 (4.1%)
Weakness	2 (4.1%)			2 (4.1%)
Arrhythmia	1 (2%)			1 (2%)
Chest pain	1 (2%)			1 (2%)
Dry Mouth	1 (2%)			1 (2%)
Dyspepsia	1 (2%)			1 (2%)
Flu-like symptoms	1 (2%)			1 (2%)
Hematuria	1 (2%)			1 (2%)
Hypertension	1 (2%)			1 (2%)
Numbness	1 (2%)			1 (2%)
Petechiae/purpura	1 (2%)			1 (2%)
Rash/desquamation	1 (2%)			1 (2%)
Thromboembolism (DVT)	0	1 (2%)		1 (2%)
Hematologic
Platelets	16 (32.7)	11 (22.4%)	19 (38.8%)	46 (93.9%)
Neutrophils (ANC)	17 (34.7%)	12 (24.5%)	11 (22.4%)	40 (81.6%)
Febrile neutropenia		1 (2%)		1 (2%)
Leukocytes (total WBC)	17 (34.7%)	15 (30.6%)	6 (12.2%)	38 (77.6%)
Hemoglobin	21 (42.9%)	5 (10.2%)	1 (2%)	27 (55.1%)

Abbreviations: CTCAE = Common Toxicity Criteria and Adverse Events; ALT = alanine aminotransferase; AST = aspartate aminotransferase; NOS = not otherwise specified; DVT = deep vein thrombosis; WBC = white blood count; ANC = absolute neutrophil count

Anti-tumor Effects and Survival:

Overall, 8 (16.3%) experienced ≥ 50% best decline in PSA from baseline, 16 (32.7%) ≥ 30% decline, and 27 (55.1%) any PSA decline without need for repeat value for confirmation [Table 3]. At the higher RP2D, 87.5% had some PSA decline, 58.8% >30% decline, 29.4% >50% best PSA decline. Each subject’s best PSA response is depicted in Figure 1. A dose-response relationship was observed, with a higher frequency of any, ≥30%, and ≥50% best PSA declines with higher doses. Median time to progression (TTP) ranged from 7 to 81.3 weeks with median TTP 16.7 weeks [95% CI 14.4 – 21]. Of 23 subjects with measurable disease at baseline, 14 (60.8%) had stable disease and 6 (26.1%) had progressive disease by RECIST; 3 withdrew from treatment and received alternative therapy prior to follow up imaging.

Table 3.

Cohort	ALL	Low (1–4)	RP2D (5–6)	5	6
Dose (mCi/m2)	20–45 ×2	20–35 ×2	40–45 ×2	40 ×2	45 ×2
N	49	16	33	16	17
Any PSA decline	55.1%	37.5%	66.7%	50%	87.5%
>30% PSA decline	32.7%	12.5%	42.4%	25%	58.8%
>50% PSA decline	16.3%	6.3%	25%	12.5%	29.4%
Median Survival [95% CI]	23.6 mo [15.0–32.2]	14.6 mo [9.9–19.4]	27.8 mo [11.1–44.3]	19.6 mo [9.5–29.8]	42.3 mo [19.9–64.7]
Platelet Gr 3	22.4%	6.3%	30.3%	31.3%	29.4%
Platelet Gr 4	38.8%	12.5%	36.4%	43.8%	58.8%
Plt Transfusion	28.6%	0	42.4%	31.3%	53%
Neutropenia Gr 3	24.5%	18.8%	27.2%	31.3%	23.5%
Neutropenia Gr 4	22.4%	0	33.3%	31.3%	35.3%
GCSF use	12.2%	0	18.2%	25%	11.8%

Abbreviations: mCi = millicurie; PSA = prostate specific antigen; Gr = grade; Plt = platelet, GCSF = granulocyte stimulating factor

Figure 1:

PSA waterfall plot

Each individual subject’s best PSA response on study. Those subjects treated with lower doses (20–35 mCi/m² ×2) of ¹⁷⁷Lu-J591 (Cohorts 1–4) are indicated in light gray while those that received recommend phase 2 doses are indicated in blue (40 mCi/m² ×2, Cohort 5) or red (45 mCi/m² ×2, Cohort 6).

Overall survival for the entire treated population was 23.6 months [95% CI 15.0 – 32.2] and was significantly longer in the higher dose cohorts, including median OS of 42.3 months [19.9–64.7] in the 45 mCi/m² × 2 cohort [Figure 2, Table 3]. As additional drugs were approved during and following the conduct of the phase II portion of the study, survival analysis was conducted utilizing CALGB (Halabi) prognostic nomogram and accounting for receipt of life-prolonging therapy (defined as docetaxel, sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, radium-223) after ¹⁷⁷Lu-J591. CALGB prognostic scores tended to associate with survival (p=0.07) and subsequent receipt of life-prolonging therapy led to longer OS (p=0.002). In multivariate analysis, administered dose associated with longer OS when controlling for CALGB prognostic score and receipt of subsequent life-prolonging therapy with hazard ratio for death 0.53 [95% CI 0.28–1.01, p=0.053].

Figure 2:

Overall survival

Probability of survival by dose received. Panel A represents the low dose cohorts (40–70 mCi/m² cumulative) vs RP2D cohorts. Panel B represents the two RP2D cohorts (80 and 90 mCi/m² cumulative). [OS:overall survival; mo: months]

Twenty-five in the phase II portion of the study had evaluable CTC counts at baseline and follow-up. Fourteen (56%) declined, 8 (32%) remained undetectable, and 3 (12%) increased [Supplemental Figure 1]. Of the 12 with baseline unfavorable CTC counts (≥ 5), 8 converted to favorable, 2 declined and 2 increased.

Imaging:

Thirty-nine of 49 (79.6%) had ¹⁷⁷Lu-J591 uptake on planar imaging in known sites of disease when compared to baseline CT/MRI and bone scan images, though those with liver metastases were difficult to assess because of the radiolabeled antibody’s hepatic clearance [Figure 3]. PSMA PET imaging was not available at the time of this trial. We analyzed semi-quantitative imaging with visual scores (VS)¹¹ and response: those with VS of 0–1 tended to have a lower (21.1%) proportion with ≥30% PSA decline than those with VS 2–4 (40.0%), p=0.17.

Figure 3:

Imaging

Left: ¹⁷⁷Lu-J591 scan: Anterior (A) and posterior (B) total body images obtained via dual head gamma camera of sites of uptake 7 days after ¹⁷⁷Lu-J591 administration. Right: ^99mTc-MDP bone scan: Anterior (C) and posterior (D) images of pretreatment bony metastases. (Note: Radiolabeled antibody is partially cleared via the liver resulting in non-specific ¹⁷⁷Lu localization).

Toxicity:

Treatment emergent toxicities are described in Table 2. As expected, myelosuppression was dose-limiting, with the majority experiencing hematologic toxicity (all grade anemia in 55.1%, neutropenia in 81.6%, thrombocytopenia in 93.9%). Grade 4 thrombocytopenia occurred in 19 (38.8%), with platelet nadir at day 41, lasting a median of 6 days (range 2–23); 14 received platelet transfusions (median 2, range 1–7 transfusions). There were no high grade hemorrhagic episodes. Fourteen of 19 (73.7%) experienced complete platelet recovery within a median of 26 days. Three experienced recovery to Gr 1, all with concurrent progressive disease by PSA. Two with partial platelet count recovery (i.e. increase from nadir) and subsequent decline had concurrent PSA rises and significant PC infiltration with scant non-dysplastic hematopoietic elements on bone marrow biopsy. Eleven (22.4%) experienced Gr 4 neutropenia up to 17 days in duration (median 7, range 1–17 days); 1 had febrile neutropenia. Six (12.2%) received filgrastim or pegfilgrastim. Hematologic toxicity was greater in the 45 mCi/m² ×2 cohort (Table 3) with significantly more platelet transfusions and grade 4 neutropenia. Prior receipt of chemotherapy, radiation, sites of metastatic disease, and amount of uptake on PSMA imaging were not associated with toxicity.

Without pre-medication, 18 subjects (36.7%) experienced transient, reversible infusion reactions consisting of feelings of warmth (with or without temperature changes), cold (without episodes of hypothermia), flushing, rigors, or elevation of blood pressure. One subject with grade 2 reaction after the 1^st dose withdrew from treatment. Twenty three (46%) had low grade fatigue, 13 (26.5%) low grade nausea, and 10 (20.4%) experienced transient grade 1–2 transaminase elevation.

DISCUSSION

As PC frequently metastasizes to bone and is radiosensitive, it is not surprising that bone targeted radioisotopes have utility,^1–3 but targeting tumor directly offers obvious potential benefits. PSMA is an ideal tumor target as detailed above. In addition, PSMA expression increases as AR signaling is dysregulated or inhibited, so resistance to AR-targeted therapies such as abiraterone and enzalutamide results in upregulated PSMA expression.^18–20 We showedthe ability to target PC with radiolabeled J591 and demonstrated efficacy with a dose-response effect with ¹⁷⁷Lu-J591, with dose-limiting thrombocytopenia.^6–8,10,11

In this study, we report that a higher cumulative dose of ¹⁷⁷Lu can be delivered by dose-fractionation with acceptable toxicity. Of note, dose-fractionation is conceptually different than re-treatment, aiming to deliver a higher cumulative amount of radiation in a single cycle without allowing for tumor repopulation between doses. Our prior dose-response relationship was confirmed, with more PSA declines and longer overall survival with higher total administered doses. This is consistent with prior dose-response data in large radiation studies.^21,22 However, there is also a clear dose-toxicity relationship. Fortunately, the timing of myelosuppression is predictable, generally short-term and self-limited; it is manageable with growth factors/transfusion when necessary with uncommon bleeding or infection, and this fractionated dose regimen may be safely delivered with concurrent docetaxel chemotherapy.²³ Many observers have commented that myelosuppression will limit further development of monoclonal antibody-based radioimmunotherapy. Here we detail the severity, duration, and consequences of our hematologic adverse events, have included an analysis of subsequent therapy with our overall survival results, and are comfortable with the proportion with high grade thrombocytopenia and need for platelet transfusions. Furthermore, we have published our long-term follow up of 150 patients treated with ¹⁷⁷Lu-J591 or ⁹⁰Y-J591, with all patients having complete neutrophil count recovery and 97.3% with platelet count recovery to grade 0–1; ¹⁷⁷Lu-J591 RIT did not prevent subsequent chemotherapy.²⁴

Targeting of PSMA with radiopharmaceuticals has increased with the use of PSMA ligands, initially for imaging and subsequently for treatment. While no direct comparisons can be made due to different patient populations with access to different additional treatments and different methodology, it is of interest to put our study into current context. Most radioligand publications have been retrospective, without clearly defined entry criteria, treatment regimens, or follow up. The largest published experience is a retrospective 12 center case series of 145 patients with mCRPC treated with ¹⁷⁷Lu-PSMA-617 which appears to provide evidence of efficacy and safety, but many patients did not have data for response or toxicity assessment.²⁵

More recently, results of the first prospective study of ¹⁷⁷Lu-PSMA-617 were published.²⁶ Australian investigators enrolled 43 men with mCRPC and treated 30 (excluding 7 (16%) due to imaging results). Following PSMA and FDG PET/CT, subjects received 4–8 GBq of up to 4 planned doses of ¹⁷⁷Lu-PSMA-617. Seventeen (57%) had at >50% PSA decline with 97% having any PSA decline; 82% with measurable disease had objective response by RECIST. Median PFS was 7.6 months and OS 13.5 months. In this prospective study, as expected with rigorous monitoring, adverse events were more common than previously reported retrospectively. Xerostomia (grade 1–2) was common at 87%, fatigue 53%, nausea 50%, and other AEs in the minority. All cause grade 3/4 anemia occurred in 23%, neutropenia 7%, thrombocytopenia 27%, though attributable toxicity was lower. An additional prospective study has been reported in abstract form utilizing the same drug, but with escalated doses administered in a single fractionated cycle with similar preliminary results.²⁷

The selective high prevalence of PSMA expression makes it a target of interest in PC. Importantly, the biodistribution of radiolabeled anti-PSMA mAb differs from that of radioligand therapy due to different mass and pharmacokinetics. While the DLT of radiolabeled antibodies is myelosuppression (with non-specific bone marrow exposure over many days as a high blood flow organ), PSMA expression in normal tissues (including renal tubules and salivary glands) is not targeted due to a combination of luminal location of PSMA expression, intervening tight junction barriers, and antibody mass. The long circulation times of mAb-based RIT is a disadvantage when it comes to myelosuppresion, but is advantageous for continuous delivery and uptake of radionuclides by tumor over many days. In contrast to the high incidence of low grade xerostomia in prospective studies of ¹⁷⁷Lu-targeted radioligand therapy, we have not observed this phenomenon (nor targeting of salivary glands by imaging).^{6–8,10,11,24,28} Renal toxicity is a potential late side effect of PSMA-radioligand therapy.²⁹ No long term follow up has been performed with PSMA-targeted radioligand therapy, but we have not observed any significant acute or delayed nephrotoxicity in our studies with many years of follow up.^{6–8,10,11,24}

Approximately 90% of PC expresses PSMA, but the incidence of AR and PSMA negative tumors may be increasing and heterogeneity exists.^30,31 We have not selected patients/tumors based on PSMA expression primarily so we would be able to evaluate response across the full spectrum of PSMA expression levels. In our prior single-dose ¹⁷⁷Lu-J591 study, we observed a trend toward lower likelihood of response in those with poorer uptake on planar/SPECT imaging in both retrospective (¹⁷⁷Lu) and prospective (¹¹¹In) imaging cohorts (prior to the availability of PSMA PET). In this study as well, patients with low visual scores had a lower likelihood of response, though there were still some responses in those with no or minimal uptake. Patient selection is an ongoing issue to be addressed in current and future studies of anti-PSMA therapeutics and it is possible that response rates will be higher in a selected population.

Sequential prospective radiolabeled J591 clinical trials have demonstrated targeting, dose-response, and improved ability to deliver higher doses with fractionation. With the recent favorable data on PSMA radioligands confirming the value of PSMA targeting and radionuclide therapy, our current goal is to further optimize this therapeutic approach with a series of early phase trials running in parallel.^27,32 Importantly, several randomized studies are in progress including a phase III trial of best standard care with or without ¹⁷⁷Lu-PSMA-617 [VISION, NCT03511664], ¹⁷⁷Lu-PSMA-617 versus cabazitaxel [TheraP, NCT03392428], and ¹⁷⁷Lu-J591 vs ¹¹¹In-J591 (control) in non-metastatic (M0) CRPC [NCT00859781].

CONCLUSIONS

Targeting metastatic castration-resistant tumors with radiolabeled anti-PSMA antibody J591 has antitumor efficacy. Our hypothesis that a higher cumulative dose could be safely delivered with a dose-fractionation strategy is confirmed. Myelosuppression remains the dose-limiting toxicity, with predictable and manageable neutropenia and thrombocytopenia. A relationship exists between administered dose and efficacy (PSA declines and overall survival) as well as toxicity.