Prostate-specific Membrane Antigen Research Articles

Are we ready to use PSMA as a theranostic biomarker in clinical practice for patients with breast cancer?

e13114 Background: Subtype classification for breast cancer (BC) patients is important for risk-stratification. Unfortunately, this parameter is not able to discriminate perfectly between high- and low-risk disease and the identification of an accurate biomarker to determine aggressiveness is still a clinical need. Prostate-specific membrane antigen (PSMA) could be important given that it has been reported to be expressed in BC tumor cells and even more in endothelial cells of tumor vessels. Methods: We analyzed 101 BCs of whom 22 luminal A, 34 Luminal B, 22 HER2 positive and 23 triple negative (TN) BC to assess whether PSMA expression by immunohistochemistry was different in tumor subtypes and was related to ki67 expression and stromal (tumour-infiltrating lymphocytes) TILs. PSMA positivity was calculated as the number of positive vessels on 10 fields at 40X magnifications. Kruskal Wallis’s test was used to assess difference in PSMA positivity among BC subgroups and Dunn’s test was performed for post-hoc comparisons; Spearman’s rho coefficient was calculated to analyze the correlation among PSMA, KI67 and TILs. Results: The median age at diagnosis of BC patients was 66 (min-max: 25-87 years). Seventy (69.3%) patients had ER>0 and 64 (63.4%) had PgR>0. The ductal histotype was present in 92 patients (91%). The majority of the patients had grade 3 tumors (55.4%). Considering the number of positive vessels, our results showed that median PSMA was higher in TNBC compared to Luminal A, Luminal B and HER2 positive tumors (p<0.001, p=0.001 and p=0.041, respectively). Ki67 was higher in TNBC compared to Luminal A, Luminal B and HER2 positive tumors (p<0.001, p<0.001 and p=0.001, respectively). We saw a correlation between PSMA and ki67, especially in HER2 positive tumors (p<0.001), while a correlation between PSMA and TILs was observed in Luminal A (p=0.028). The analysis of PSMA expression on the lymph nodes showed the same trend observed for the primary tumors given that it was higher in TNBC compared to HER2 positive and luminal cancers. Conclusions: Our results suggest that PSMA could be used as a theranostic biomarker in BC considering that it is highly expressed in more aggressive tumors and the possibility to treat PSMA expressing patients for anti-angiogenesis and/or radionuclide treatment.

Quality metrics analysis in patients who received Lutetium-177 PSMA-617 (177Lu–PSMA) therapy in a real-world practice setting.

e17049 Background: 177Lu–PSMA is a radiolabeled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA). It has been approved for use in metastatic castration-resistant prostate cancer (mCPRC) in 3/2022, based on VISION study. The Food and Drug Administration (FDA) label for 177Lu–PSMA requires prior therapy with an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy as well as presence of at least one PSMA-positive tumor with uptake greater than normal liver and no PSMA-negative lesions on a PSMA positron emission tomography (PET) scan. In the VISION study, PSMA PET was performed within 4 weeks of therapy start. Further, patient received either 177Lu–PSMA plus protocol permitted standard of care (SOC), including ARPI, or SOC alone. Given the relatively recent approval of this therapy, real-world familiarity with administration of this agent may not be optimal. Methods: A retrospective analysis of 25 patients with mCRPC who received 177Lu–PSMA therapy since 3/2022 at the University of California Irvine (24/25) and Hoag Hospital (1/25) was performed. Multiple variables were analyzed and compared to the FDA label for this agent as well as design of the VISION study. Results: All patients in this study had received an ARPI and at least one taxane chemotherapy prior to 177Lu–PSMA. A PSMA-PET scan was obtained prior to 177Lu–PSMA therapy in all patients. The timing of the scan was within 4 weeks of starting 177Lu–PSMA therapy in only 5/25 (20.0%) patients. The average time from PSMA PET scan to 177Lu–PSMA therapy start was 66 days [range: 18 - 326 days]. None of the PSMA PET scan reports included a baseline liver standardized uptake value (SUV) or mentioned whether any lesions were non PSMA-avid. All reports provided SUV values for some, but not all, PSMA-avid lesions. The average maximum SUV of the most PSMA-avid lesion noted on the reports was 34.7. All PSMA PET scans were retrospectively reviewed by a nuclear medicine specialist and the average maximum SUV of the most PSMA-avid lesion on re-review was 42.0 (p <0.05). During 177Lu–PSMA therapy, co-administration of ARPI occurred in 10/24 (23.8%) of patients. Conclusions: This study highlights the differences in quality metrics between patients who received 177Lu–PSMA therapy in a real-world practice setting compared to the FDA label for this agent and VISION study design. Differences included lack of uniform PSMA PET scan reporting, timing of obtaining pre-treatment PSMA PET imaging, and co-administration of ARPI. Development of institutional algorithms around administration of 177Lu–PSMA therapy may be needed.

Imaging and clinical characteristics of incidental abnormal thyroid uptake on PSMA PET/CT.

e18077 Background: To investigate the incidence, features, and clinical characteristics of unexpected prostate-specific membrane antigen (PSMA) uptake within the thyroid gland of patients with prostate cancer (PCa) who underwent F-18 DCFPyL PSMA PET/CT. Methods: We retrospectively reviewed a cohort of 1148 PCa patients who underwent PSMA PET/CT at our institution between 11/2021 - 09/2023. Scans with abnormal thyroid uptake were identified. Clinical data included patient demographics, PCa history, Gleason score, prostate specific antigen (PSA), ultrasonography (US), fine needle aspirate (FNA) / thyroidectomy, histopathology, and history of neck radiation or prior malignancy. Each scan was further analyzed with lesion-specific iso-contour method (42% cutoff) to obtain PET parameters (most prominent nodule SUVmax, SUVmean, PSMA volume, tumor lesion PSMA, contralateral gland SUVmax, SUVmax-nodule / SUVmax-contralateral gland ratio, most prominent PCa lesion SUVmax), PCa tumor distribution, and tumor volume. CT-related variables (nodule number, dominant nodule size, short/long axis ratio, CT-HU, integral total value) were also collected. Pearson's chi-square testing and Kruskal-Wallis testing was performed for categorical and nonparametric data respectively. Receiver operating characteristic (ROC) curves with area under curve (AUC) value were determined using IBM SPSS (version 29.0). Results: Of the 1148 PSMA PET/CTs, 60 (5.2%) had abnormal thyroid uptake (nodular: 58, diffuse: 2). Diffuse uptake was found to represent thyroiditis in both patients. 43 (56.7%) had an US, 20 (33%) were biopsied (11 benign, 5 indeterminate, 4 malignant), and 5 (8.3%) pursued thyroidectomy (3 malignant, 2 benign). 22 patients (36.7%) had histopathology data and 5 malignancies (2 PCa, 1 CLL, 2 primary thyroid) were identified. Nodule size was larger in those who had an US relative to those who did not. Among those with US data, no significant differences in clinical or histopathological parameters were seen. SUVmax (p: 0.01; AUC: 0.876, 95%CI: 0.731-1.0) and SUVmean (p:0.01; AUC: 0.871, 95%CI: 0.722-1.0) were higher in the malignant group. Nodule SUVmax/contralateral gland SUVmax ratio showed borderline significance (p = 0.05). Conclusions: Incidental PSMA PET uptake in the thyroid gland is seen in approximately 5% of patients. Focal uptake should prompt consideration of US and FNA due to the possibility of prostate cancer metastasis and thyroid cancer. SUVmax/mean is higher in malignant lesions.

Prostate-specific membrane antigen PET/CT-guided, metastasis-directed radiotherapy for oligometastatic castration-resistant prostate cancer.

e17057 Background: Systemic treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (ARPIs), chemotherapy, and radiopharmaceutical therapy, all of which have associated toxicity. We hypothesized that prostate-specific membrane antigen (PSMA) PET/CT-guided, metastasis-directed radiotherapy may offer durable disease control with low toxicity rates in patients with mCRPC who have a limited number of metastatic sites. Methods: We retrospectively screened 7 prospective databases of PSMA PET/CT scans conducted between 1/2016-2/2023 for patients with mCRPC who had ≤5 sites of oligorecurrent or oligoprogressive disease and received metastasis-directed radiotherapy to all sites of disease. Castration resistance was defined as either radiographic progression or biochemical progression (two consecutive prostate-specific antigen [PSA] increases ≥3 weeks apart) while on ADT with serum testosterone <50 ng/dL. Progression-free survival (PFS), freedom from new lines of systemic therapy, and overall survival (OS) were calculated from the start of metastasis-directed radiotherapy using Kaplan-Meier analysis. Progression was defined as the first instance of biochemical progression (PSA increase of 25% and 2 ng/mL above nadir, confirmed by repeat measurement ≥3 weeks later), radiographic progression, biopsy-proven recurrence, new systemic or local therapy, or death. Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 5. Results: Twenty-six patients met inclusion criteria with a median follow-up of 34.6 months (interquartile range, 28.1-47.2 months). All patients previously received ADT, 20 (77%) received ARPIs, and 3 (12%) had prior chemotherapy. Median PSA was 1.2 ng/mL, median time from initial diagnosis was 6.2 years, and median time from castration resistance was 1.8 years. Between 10/2017-4/2023, 12 patients (46.2%) had one treated metastatic site, 11 patients (42.3%) had two, and 3 patients (11.5%) had three. Twenty-four patients (92.3%) received concurrent systemic therapy. Median PFS was 16.4 months (95% confidence interval [CI], 11.4-21.4 months). Four-year PFS was 26.7% (95% CI, 8.9-44.5%). Median time to initiation of a new line of systemic therapy was 18.0 months (95% CI, 0-36.2 months). Four-year freedom from new lines of systemic therapy was 36.1% (95% CI, 15.5-56.7%). Median OS was not reached. Four-year OS was 72.5% (95% CI, 51.1-93.9%). Grade 2 and ≥3 toxicity rates were 3.8% and 0%, respectively. Conclusions: For patients with oligometastatic CRPC, PSMA PET/CT-guided metastasis-directed radiotherapy appears to offer durable disease control with low toxicity. Further prospective studies are needed to compare PSMA PET/CT-guided versus conventional imaging-guided radiotherapy.

Phase 1 clinical trial of AMG 340, a prostate-specific membrane antigen (PSMA)-targeted T-cell engager with a novel low-affinity CD3 binding domain designed to mitigate toxicity for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

e14587 Background: PSMA, a transmembrane protein highly expressed on the surface of prostate cancer cells, is a validated target in prostate cancer; however, achieving a favorable therapeutic index has been challenging for PSMA-directed T-cell engagers (TCE’s). AMG 340, a PSMA-targeted TCE with a novel low-affinity CD3 binding domain specifically engineered to mitigate cytokine release syndrome (CRS) toxicity and maintain efficacy was investigated in a phase 1, open-label, dose-escalation study (NCT04740034). Methods: Patients (pts) with mCRPC who had received ≥2 prior lines of therapy were treated with AMG 340 monotherapy (1.5–800 mg intravenously every 3 weeks [Q3W]) during dose escalation. The primary outcome measures were dose-limiting toxicities, treatment-emergent adverse events (TEAEs), and pharmacokinetic profile. Secondary outcomes included prostate antigen specific (PSA) response and objective response per response evaluation criteria in solid tumors (RECIST). Results: As of September 6, 2023, a total of 42 pts (mean ± SD age, 68.5±7.8 years) received AMG 340 step up dosing across 11 cohorts. At doses up to 800 mg Q3W, AMG 340 had a manageable side effect profile. Any grade TEAEs reported in ≥30% of pts included CRS (52%), nausea (52%), vomiting (52%), fatigue (48%), diarrhea (38%), increased aspartate aminotransferase (36%), increased alanine aminotransferase (33%), and hypocalcemia (31%). Treatment-related toxicities included CRS (52%; Grade 1, 26%; Grade 2, 24%; Grade ≥3, 2%) and thrombocytopenia (24%; Grade 2, 10%; Grade ≥3, 14%). Step dosing was implemented at doses >40 mg and successfully mitigated CRS incidence and severity after the first dose. The maximal tolerated dose was not reached, as increasing the dose beyond 800 mg was predicted to minimally increase the potential AMG 340 activity. Exposure increased in an approximately dose-proportional manner with no evidence of clinically significant anti-drug antibodies. AMG 340 demonstrated evidence for pharmacodynamic engagement as shown by cytokine induction. Of the 41 PSA evaluable pts, PSA responses were seen across dose levels (PSA50, n=4), but were not dose dependent. Eight of 42 pts remained on treatment after 6 months. Among 27 RECIST evaluable pts, no RECIST responses were observed (n=14 stable disease, n=0 partial or complete response). Conclusions: Despite reaching high doses, no dose response was observed, and AMG 340 did not generate sufficient clinical activity to warrant further exploration. However, AMG 340 demonstrated manageable CRS toxicity showing that decreased CD3-binding strength mitigates CRS, the main toxicity of TCEs. Clinical studies are ongoing evaluating the PSMA protein as a molecular target for prostate cancer. Clinical trial information: NCT04740034 .

Dosimetry of lutetium-177-PSMA-I&T radioligand therapy in recurrent/metastatic adenoid cystic carcinoma.

6093 Background: There is a high unmet need for effective systemic therapies for recurrent and/or metastatic (R/M) adenoid cystic carcinoma (AdCC), as no standard-of-care exists. AdCC frequently expresses prostate-specific membrane antigen (PSMA), providing rationale for PSMA-targeted therapies, which have demonstrated significant efficacy in prostate cancer. In our phase 2 pilot trial (EudraCT 2019-003857-27), we assessed the safety, efficacy and feasibility of lutetium-177 (177Lu)-PSMA-I&T in R/M AdCC patients. Despite well-tolerated, the efficacy was limited. To gain further insight into causes of the limited efficacy, we measured absorbed 177Lu-PSMA-I&T radiation doses in tumors and organs at risk. Methods: Dosimetry was feasible and was performed in all 10 enrolled AdCC patients. They received 177Lu-PSMA-I&T with a median activity of 7.40 (range 6.78-7.49) GBq and a median of 4 (range 1-4) cycles. For bone marrow dosimetry, blood samples were collected during cycle 1. Single-photon emission CT/CT (SPECT/CT) was performed at 1, 24, 48, 72 and 168 hours after 177Lu-PSMA-I&T injection at cycle 1. Tumors >1 cm were categorized based on gallium-68 (68Ga)-PSMA PET mean standardized uptake value (SUVmean): above, at (±10%), and below liver SUVmean. Per site, up to 3 index lesions per category were selected. Volumes of interest with ~1 cm margin were drawn on SPECT/CT. Background correction was applied. Salivary gland and bone lesion volume were determined by iterative thresholding on 68Ga-PSMA PET. Other tumor volumes were determined on CT. Hermes dosimetry software and Olinda 2.2 software were used to estimate doses according to the Medical Internal Radiation Dose scheme. Results were reported as the absorbed dose at cycle 1 (Gy). Results: In total, 66 tumor lesions were analyzed. Tumor sites included lung (n=35), pleura (n=16), liver (n=5), bone (n=4), lymph node (n=3), local recurrence (n=2) and thoracic wall (n=1). The median 68Ga-PSMA PET tumor/liver SUVmean ratio was 0.94 (range 0.33-2.62). The median tumor-absorbed dose was 0.47 (range, 0.01-4.66) Gy. Highest median doses by tumor site were 1.84 (range, 0.76-2.92) Gy in local recurrences and 1.35 (range, 0.33-2.62) Gy in bone lesions. Lowest median doses by tumor site were 0.18 (range, 0.14-0.27) Gy in lymph node lesions and 0.21 (range, 0.12-0.79) Gy in liver lesions. In organs at risk, the absorbed dose was highest in the kidneys, followed by the salivary glands, with mean values of 6.29 (standard deviation [SD], 2.32) Gy and 5.07 (SD, 2.47) Gy, respectively. The mean bone marrow absorbed dose was 0.53 (SD, 0.14) Gy. Conclusions: Tumor-absorbed radiation doses in our AdCC patient cohort receiving 177Lu-PSMA-I&T were significantly lower than in prostate cancer (~10-40 Gy per cycle), likely due to lower and heterogeneous PSMA expression. This could explain the limited efficacy. Organ-absorbed doses aligned with studies in prostate cancer. Clinical trial information: NCT04291300 .

Xerostomia and ocular dryness as predictors of PSA response to Lu177-PSMA-617 in metastatic castration resistant prostate cancer.

e17028 Background: Prostate specific membrane antigen (PSMA) is highly expressed in salivary and lacrimal glands. Dry eyes and/or mouth can occur with Lu177-PSMA-617 (PSMA Lu177) therapy in metastatic castration resistant prostate cancer (mCRPC) pts. We evaluated the difference between the presence of dry mouth/eyes with PSA responses in pts with mCRPC treated with PSMA Lu177. Methods: The Indiana University Prostate Cancer database was queried for pts with mCRPC who were treated with PSMA Lu177. Toxicities were documented throughout the course of treatment. Association of xerostomia and ocular dryness with PSA30 and PSA50 response was compared using the Chi Square test, or Fisher’s Exact test, if more appropriate. Results: Between 6/21/22-11/14/23, 107 pts with mCRPC were treated with PSMA Lu177 with at least 2 doses. Median age was 73 (56, 90). 86 pts had metastatic disease in bone, 65 lymph nodes, 11 lungs, 6 liver, and 2 brain. 39 pts had 1 prior ARPI, 68 pts had ≥2 prior ARPI. 17 pts had no prior taxane regimen, 45 had 1 prior taxane, 33 had 2 prior taxanes and 12 had ≥3 taxane regimens. 19 pts had prior PARP inhibitor. Median follow-up from start of PSMA Lu177 treatment was 8.3 months (1.4-18.7). 40 (37%) pts experienced dry mouth, 7 (7%) pts experienced dry eyes, and 6 (6%) pts experienced both. 65 (61%) pts achieved PSA30 response. 57 (53%) pts achieved PSA 50 response. Conclusions: The presence of dry eyes and/or dry mouth in pts with mCRPC treated with PSMA Lu177 was associated with improved PSA response. [Table: see text]

Development of small molecule–drug conjugates based on derivatives of natural proteasome inhibitors that exhibit selectivity for PSMA-expressing cancer cells

In this study, we have developedsmall molecule drug conjugates (SMDCs)consisting ofa prostate specific membrane antigen (PSMA) ligandand syringolin derivatives, which are potent proteasome inhibitors, to selectively deliver syringolin derivatives to prostate cancer cells. Two parent compounds were used for syringolin derivatives with different linkage sites. These SMDCs exhibited PSMA-expressing cell-selective cytotoxicity and they could potentially be used for safer treatment of cancer.

Prostate-specific membrane antigen (PSMA) radio-guided surgery in prostate cancer: expanding the spectrum of tracers and technologies for patient-tailored molecular-guided surgery

Prostate-specific membrane antigen (PSMA) radio-guided surgery in prostate cancer: expanding the spectrum of tracers and technologies for patient-tailored molecular-guided surgery

Emerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy.

The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer targeting carbonic anhydrase IX and prostate-specific membrane antigen are under development to detect primary kidney tumors, stage systemic disease, and assess treatment response in RCC. Immune checkpoint inhibitors targeting PD-1 and cytotoxic T-cell lymphocyte-4 have changed the treatment paradigm in advanced RCC. Trials investigating novel mechanisms such as LAG-3 immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and T-cell engagers targeting RCC-associated antigens are currently ongoing. With the rapidly changing treatment landscape of RCC, the treatment sequence strategies will continue to evolve. Familiarity with the toxicities associated with the therapeutic agents and how to manage them are essential to achieve optimal patient outcomes. This review summarizes the recent developments of functional imaging and immunotherapy strategies in RCC, and the evidence supports treatment sequencing.

Patient characteristics, treatment patterns and early trends of lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) use by US urologists and oncologists.

e17048 Background: 177Lu-PSMA-617 was approved by the US Food and Drug Administration in March 2022 for the treatment of patients with prostate-specific membrane antigen (PSMA) positive metastatic castration resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition (ARPI) and taxane-based chemotherapy. This study describes characteristics of patients treated with 177Lu-PSMA-617, treatment patterns and early trends in 177Lu-PSMA-617 utilization by US urologists (URO) and medical oncologists (ONC). Methods: This retrospective cohort study identified adult patients with ≥1 claim for 177Lu-PSMA-617 between 3/1/22 and 6/30/23 (first claim = index date) from the IQVIA open-source pharmacy and medical claims database. Patients were grouped by the physician specialty of the treating/referring physician. Patient characteristics were assessed within the 6 months prior to 177Lu-PSMA-617 initiation. Prior prostate cancer treatments were assessed over all available pre-index data. Results: Overall 1,394 patientstreated with 177Lu-PSMA-617 were identified during the first 16 months post-approval; 76.9% treated by an ONC and 23.1% treated by a URO. The mean age overall was 72.1 years; most patients were aged 65 and older (ONC, 83.3%; URO, 84.8%). Most patients had bone metastases (ONC, 88.0%; URO, 86.3%) and over one-third had visceral metastases (ONC, 34.6%; URO 35.7%). URO treated a higher proportion of patients with only lymph node metastases (5.9%) than oncologists (2.6%). Prior to 177Lu-PSMA-617, the vast majority of patients received ARPI and/or taxanes (ONC, 88.2%; URO, 89.4%). Use of 177Lu-PSMA-617 has steadily increased over the 16 months since approval with over five times as many patients being treated by ONC and URO in the first half of 2023. Conclusions: This is the first large-scale study describing 177Lu-PSMA-617 patient characteristics, prostatic cancer metastatic distribution, treatment patterns, and utilization trends by prescriber type (ONC and URO). This study highlights how URO are playing a pivotal role in management of post-taxane mCRPC patients receiving 177Lu-PSMA-617. As additional data with 177Lu-PSMA-617 becomes available, we anticipate the role of URO to significantly evolve with the potential for earlier use of 177Lu-PSMA-617 for pre-taxane mCRPC patients.

Real-world treatment landscape in advanced metastatic castration resistant prostate cancer.

e17032 Background: Despite a rapidly evolving treatment landscape in advanced prostate cancer (aPC) marked by recent emergence of therapies such as radioconjugates and PARP inhibitors, outcomes remain poor for many patients. Future care improvements will require innovative treatments and simplifying treatment planning. The goal of this study is to understand how the evolving treatment landscape has impacted care and outcomes in patients with aPC using real world (rw) data. This study evaluates outcomes of mCRPC patients who have advanced to a 3rd line of therapy (L3) with prior exposure to both an androgen receptor signaling inhibitor (ARSI) therapy and a taxane or platinum-based chemotherapy, in any aPC disease setting. Methods: mCRPC patients in the Flatiron Database who progressed to L3 with pre-L3 exposure to both an ARSI (abiraterone, enzalutamide, apalutamide, and darolutamide) and chemotherapy (cabazitaxel and docetaxel) were eligible for inclusion. Patients whose mCRPC diagnosis occurred between Dec 2010 and Nov 2023 were included. As the objective was to study the aPC treatment landscape, patients with prior exposure to therapies approved in the mCRPC disease setting such as radioconjugates, PARP inhibitors, radiation, investigational and palliative drugs were excluded. Outcomes were reported as median real-world overall survival (rwOS) indexed to start of L3 treatment, and median rw time to next treatment (rwTTNT) from the start of L3 to the beginning of L4 treatment. Results: 660 patients met all inclusion criteria and had at least one year of treatment history in the aPC disease setting. Median follow up time (indexed to L3 start) for all patients was 7.55 months. Median rwOS for all patients was 10.8 months (95% CI 9.9 - 12.2), while median rwTTNT was 5 months (95% CI 4.6 - 5.4). The most common L3 therapy class was chemotherapy, followed by ARSIs (Table). To aid in treatment planning strategies, drug sequence patterns were also analyzed. Frontline ARSIs were followed by second line chemotherapy for most of the patients (n = 349; 53%). Conclusions: Relatively short survival times and short durations on L3 therapies for aPC demonstrate a high unmet need, with therapeutic options dominated by ARSIs and chemotherapy. Recently approved radioconjugate therapies, like Pluvicto â, have reported median OS 15.3 months (Fallah, 2023) in prostate-specific membrane antigen (PSMA)-positive patients, which is greater than the 10.8 months observed in general mCRPC population analyzed in this study. These findings underscore the need to develop effective therapies and treatment strategies that are tailored for advanced prostate cancer. [Table: see text]

Phase I/II trial of LAVA-1207, a novel bispecific gamma-delta T-cell engager alone, or with low dose IL-2 or pembrolizumab, in metastatic castration resistant prostate cancer (mCRPC).

TPS2672 Background: LAVA-1207 is a humanized bispecific antibody that binds with high affinity to the Vδ2 chain of Vγ9Vδ2-T cells and to prostate-specific membrane antigen (PSMA). It comprises a heterodimer of two fusion proteins, each consisting of a VHH linked to a human IgG1 Fc domain. Preclinical evidence demonstrates that, upon binding both targets, LAVA-1207 leads to potent Vγ9Vδ2-T cell degranulation and cytolytic activity against PSMA-expressing prostate cancer cells. IL-2 is an immune modulator which has been shown to support expansion of activated Vγ9Vδ2-T cells. PD-1 is an inhibitory immune checkpoint receptor that can dampen (Vγ9Vδ2-) T cell reactivity, suggesting that pembrolizumab could potentiate the effect of LAVA-1207. Methods: This trial is a phase 1/2a open label study with a 3+3 design in patients with refractory mCRPC to assess the safety of LAVA-1207 alone or with low dose IL-2 or with pembrolizumab, and to determine the recommended Phase 2a dose (RP2D). Secondary objectives include evaluation of pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity. Exploratory endpoints include evaluation of the effect of study treatment on circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). LAVA-1207 is administered IV every two weeks. Two parallel cohorts assessing LAVA-1207 with low dose subcutaneous IL-2 have been implemented: (1) single IL-2 administration and (2) three IL-2 administrations on consecutive days per cycle for up to four cycles. An additional dose escalation arm evaluates LAVA-1207 in combination with pembrolizumab, 400mg Q6W, IV. Patients with mCRPC that have failed at least one prior AR therapy and taxane-based chemotherapy (unless deemed medically unsuitable to receive a taxane) will be enrolled on the study. Patients should have progressive disease either by PSA or by RECIST 1.1 or appearance of 2 or more bone metastases. Patients must have ECOG performance status of 0-1. PSMA-PET is performed at baseline. Paired biopsies are requested to further assess LAVA-1207 activity. Dose escalation is ongoing. Expansion arm(s) will be included based on available data from part 1 of the study and may include one or more of LAVA-1207, LAVA-1207 with low dose IL-2, or LAVA-1207 in combination with pembrolizumab. Clinical trial information: NCT05369000 .

Real-world PET PSMA imaging patterns in a Chicago safety-net hospital.

e17009 Background: Prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging is an FDA-approved imaging modality with increased sensitivity for prostate cancer (PCa) detection. It thus can more accurately stage patients to determine optimal initial treatment. However, patients with indications for these scans can still experience significant delays in obtaining them, mainly due to insurance denials. Such delays often disproportionately affect those with healthcare disparities, representing a substantial population at University of Illinois Chicago (UIC), a safety-net hospital. We sought to identify patterns, barriers, & areas for improvement in obtaining this guideline-directed imaging modality. Methods: PCa patients with a PSMA PET scan ordered between January 2021 and June 2023 were included for analysis. Key medical and demographic data such as age, race/ethnicity, and insurance status were obtained. We also determined the time between ordering and obtaining the PSMA PET, and whether the scan led to classifying the patient’s disease as clinically localized, regional, or metastatic. We also determined whether subsequent treatment was curative or palliative intent. The dates and types of other imaging modalities, if obtained, were also recorded. Results: We identified 76 patients with PSMA PET scans ordered during the study timeframe. The mean age was 68.6 years, with a standard deviation of 7.3 years. 60.0% identified as Black or African American, 24.0% as White, 4.0% as Asian, and 1.3% as American Indian or Alaska Native. 40.8% had Illinois Medicare as their primary insurance, 27.6% had Medicaid, and 31.6% had another medical insurance. Most individuals (77.6%) had a delay in obtaining their PSMA PET scan, with a median time to scan of 23.0 days (range 6-136). All insurance types, including Illinois Medicare, Medicaid, and private insurance, had delays (74.2%, 81.0% and 79.2% of all PSMA PETs, respectively). Many delayed individuals also received conventional imaging (46.0%) within 3 months of the PSMA PET scan order as part of their workup, with 40.0% of PSMA PETs revealing new findings compared to the other scans. Ultimately, most of the imaged patients (54.0%) were determined to have regional or metastatic PCa. Delays in obtaining and receiving the results of scans affected individuals who underwent both curative (40.8%) as well as palliative intent (46.1%) treatment. Conclusions: Between January 2021 and June 2023, PCa patients had a median delay of approximately three weeks in obtaining a PSMA PET scan that was ordered urgently for the determination of their PCa treatment. Such delays can significantly impact health outcomes and often result in redundant conventional imaging. This retrospective study represents the first step in a quality improvement project to reduce delays to PSMA PETs and enable the development of a timely treatment plan to improve patient outcomes in our diverse patient population.

Hematologic toxicity in 177lu-PSMA-617 treatment for mCRPC: Unraveling the impact of PSMA PET bone tumor volume (PSMA-bTTV).

5075 Background: Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA-617) is a life-prolonging treatment approved by the FDA in metastatic castration-resistant prostate cancer (mCRPC), at a very late stage when there frequently reduced bone marrow reserve. We aim to report the incidence of hematologic toxicity during treatment and potential risk factors in a single-center study. Methods: This retrospective single-institution case series included mCRPC patients who underwent at least one cycle of 177Lu-PSMA-617 treatment between June 2022 and January 2024. Hematological parameters were documented at baseline, 3 weeks after each treatment, and before each subsequent treatment administration. Then, we captured the nadir values for each parameter during treatment. Hematologic toxicities were assessed using the Common Terminology Criteria for Adverse Events v5.0, with Grades 3 and 4 considered significant. Multivariable logistic regression analyses were conducted to investigate the association between hematological adverse events and baseline characteristics including PSMA-bTTV, measured by semi-automatic contouring of the PSMA-expressing whole-body bone metastases on pre-treatment PSMA PET. Results: Our study included 138 mCRPC patients (median age: 73y, prior chemotherapy: 92%, prior radiation: 43.5%, bone involvement: 89.1%), who underwent a median of 3 cycles (IQR: 2-5) of 177Lu-PSMA-617 treatment. At baseline, 8 (5.8%) patients had grade 3 anemia, 2 (1.4%) patients had grade 3 leukopenia, and 1 (0.7%) patient had grade 3 thrombocytopenia. Nadir values during treatment indicated that 23 (16.7%) had grade 3 anemia, 5 (3.6%) had grade 3 leukopenia, and 11 (8%) had grade 3 and 4 thrombocytopenia. Multivariable analysis of predisposing factors for hematologic adverse events showed that the PSMA-bTTV was significantly associated with occurrence of any grade ≥3 hematologic toxicity, anemia, and thrombocytopenia after adjusting for other baseline clinical variables (Table). Conclusions: Over 1 in 5 patients with mCRPC experienced significant hematologic adverse events during treatment with 177Lu-PSMA-617. Bone tumor volume is a possible risk factor for developing significant hematologic toxicity. [Table: see text]

Photoimmunotherapy of Prostate Cancer With Antibody and Fab Fragments Targeting the Prostate Specific Membrane Antigen.

The standard treatment for localized prostate cancer involves surgical removal of the prostate with curative intent. However, when tumor cells persist in the operation site, there is high risk of local recurrence and tumor spread, leading to stressful follow-up treatments, impaired quality of life, and reduced overall survival. This study examined photoimmunotherapy (PIT) as a new treatment option for prostate cancer cells. We generated conjugates consisting of either a humanized antibody or Fab fragments thereof targeting the prostate specific membrane antigen (PSMA), along with our silicon phthalocyanine photosensitizer dye WB692-CB1. PSMA-expressing prostate cancer cells were incubated with the antibody dye or Fab dye conjugates and cell binding was measured using flow cytometry. Cells were irradiated with varying doses of red light for dye activation, and cytotoxicity was determined by erythrosin B staining and subsequent analysis using a Neubauer counting chamber. Specific cytotoxicity was induced with the antibody dye conjugate in the prostate cancer cells in a light dose-dependent manner. Treatment of the cells with the Fab dye conjugate resulted in lower cytotoxicity, which could be attributed to a reduced binding affinity and a reduced dye uptake of the Fab fragment. Our new antibody dye and Fab dye conjugates offer potential for future intraoperative PIT in patients with localized prostate cancer, with the aim to ensure complete removal of tumor cells from the surgical area, to avoid local recurrence, and to improve clinical outcome.

A systematic review and meta-analysis to evaluate the diagnostic accuracy of PSMA PET/CT in the initial staging of prostate cancer.

Positron Emission Tomography-Computed Tomography using Prostate-Specific Membrane Antigen (PSMA PET/CT) is notable for its superior sensitivity and specificity in detecting recurrent PCa and is under investigation for its potential in pre-treatment staging. Despite its established efficacy in nodal and metastasis staging in trial setting, its role in primary staging awaits fuller validation due to limited evidence on oncologic outcomes. This systematic review and meta-analysis aims to appraise the diagnostic accuracy of PSMA PET/CT compared to CI for comprehensive PCa staging. Medline, Scopus and Web of science databases were searched till March 2023. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed to identify eligible studies. Primary outcomes were specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) of PSMA PET/CT for local, nodal and metastatic staging in PCa patients. Due to the unavailability of data, a meta-analysis was feasible only for detection of seminal vesicles invasion (SVI) and LNI. A total of 49 studies, comprising 3876 patients, were included. Of these, 6 investigated accuracy of PSMA PET/CT in detection of SVI. Pooled sensitivity, specificity, PPV and NPV were 42.29% (95%CI: 29.85-55.78%), 87.59% (95%CI: 77.10%-93.67%), 93.39% (95%CI: 74.95%-98.52%) and 86.60% (95%CI: 58.83%-96.69%), respectively. Heterogeneity analysis revealed significant variability for PPV and NPV. 18 studies investigated PSMA PET/CT accuracy in detection of LNI. Aggregate sensitivity, specificity, PPV and NPV were 43.63% (95%CI: 34.19-53.56%), 85.55% (95%CI: 75.95%-91.74%), 67.47% (95%CI: 52.42%-79.6%) and 83.61% (95%CI: 79.19%-87.24%). No significant heterogeneity was found between studies. The present systematic review and meta-analysis highlights PSMA PET-CT effectiveness in detecting SVI and its good accuracy in LNI compared to CI. Nonetheless, it also reveals a lack of high-quality research on its performance in clinical T staging, extraprostatic extension and distant metastasis evaluation, emphasizing the need for further rigorous studies.

Systematic Review of the First 40 Cases of 177Lu-PSMA Therapy in the Treatment of Non-prostatic Cancer.

The current systematic review aimed to collect and analyze all available published and unpublished cases in which prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (177Lu-PSMA) was used to treat non-prostatic cancer. Literature search and evidence acquisition through contacts with organizations that use 177Lu-PSMA were employed. PubMed/Medline, SCOPUS, and ScienceDirect searches were performed following PRISMA recommendations. The search strategy was to screen all articles describing 177Lu-PSMA radioligand therapy published to date with the key word "177Lu-PSMA". These articles were collected and screened for non-prostatic cancer cases. Quality assessment was performed using the GRADE criteria. A total of 713 articles were screened, and the search revealed 15 eligible records. Forty patients with a mean age of 51.2±18.5 years were treated with 177Lu-PSMA for non-prostatic cancer. Of them, 30 cases were published, and 10 were found in medical institution records. Cancers of the salivary glands were most often targeted (13/40), followed by various brain cancer types (8/40), and osteosarcoma (6/40). The authors used previously established protocols for castration-resistant prostate cancer with the dose per cycle as 6.0-7.4 GBq and the number of cycles between one and four. Toxicity was estimated as low, and 21 out of 28 patients with reported outcomes survived to the time of the publication. PSMA-targeted radioligand therapy was infrequently used to treat different non-prostatic cancer types in various target organs. These pioneering efforts indicate that 177Lu-PSMA can be used to treat non-prostatic cancer with PSMA expression. The toxicity of such treatment was low, and the outcome was relatively good.

Spatial Distribution of Recurrence and Long-Term Toxicity Following Dose Escalation to the Dominant Intra-Prostatic Nodule for Intermediate-High-Risk Prostate Cancer: Insights from a Phase I/II Study.

Objectives: We investigated spatial patterns between primary and recurrent tumor sites and assessed long-term toxicity after dose escalation stereotactic body radiation therapy (SBRT) to the dominant intra-prostatic nodule (DIN). Materials and methods: In 33 patients with intermediate-high-risk prostate cancer (PCa), doses up to 50 Gy were administered to the DIN. Recurrence sites were determined and compared to the original tumor development sites through multiparametric MRI and 68Ga-labeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) images. Overlap rates, categorized as 75% or higher for full overlap, and 25-74% for partial overlap, were assessed. Long-term toxicity is reported. Results: All patients completed treatment, with only one receiving concomitant androgen deprivation therapy (ADT). Recurrences were diagnosed after a median of 33 months (range: 17-76 months), affecting 13 out of 33 patients (39.4%). Intra-prostatic recurrences occurred in 7 patients (21%), with ≥75% overlap in two, a partial overlap in another two, and no overlap in the remaining three patients. Notably, five patients with intra-prostatic recurrences had synchronous bone and/or lymph node metastases, while six patients had isolated bone or lymph node metastasis without intra-prostatic recurrences. Extended follow-up revealed late grade ≥ 2 GU and GI toxicity in 18% (n = 6) and 6% (n = 2) of the patients. Conclusions: Among patients with intermediate-high-risk PCa undergoing focal dose-escalated SBRT without ADT, DIN recurrences were infrequent. When present, these recurrences were typically located at the original site or adjacent to the initial tumor. Conversely, relapses beyond the DIN and in extra-prostatic (metastatic) sites were prevalent, underscoring the significance of systemic ADT in managing this patient population. Advances in knowledge: Focal dose-escalated prostate SBRT prevented recurrences in the dominant nodule; however, extra-prostatic recurrence sites were frequent.

Protocol for CHAMPION study: a prospective study of maximal-cytoreductive therapies for patients with de novo metastatic hormone-sensitive prostate cancer who achieve oligopersistent metastases during systemic treatment with apalutamide plus androgen deprivation therapy

BackgroundThe proposed trial is to examine the feasibility of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided cytoreduction plus apalutamide and androgen deprivation therapy (ADT) for newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) at oligometastatic state.MethodsCHAMPION (NCT05717582) is an open-label, single-arm, phase II trial, planning to enroll newly diagnosed mHSPC cases with oligometastases (≤ 10 distant metastatic sites in conventional imaging). Patients will receive 6 cycles of apalutamide plus ADT. Patients with oligometastatic disease at PSMA PET/CT after 3 treatment cycles will receive cytoreductive radical prostatectomy. PSMA PET/CT-guided metastasis-directed external radiation therapy will be determined by the investigators. Apalutamide plus ADT will be continued for 2 weeks postoperatively. The primary endpoint is the proportion of patients with undetectable prostate-specific antigen (PSA), no disease progression, and no symptom deterioration after 6 cycles of apalutamide plus ADT. Secondary endpoints include the percentage of patients with PSA ≤ 0.2 ng/mL and oligometastases by the end of 3 treatment cycles, PSA response rate, and safety. Fleming’s two-stage group sequential design will be adopted in the study, where the null hypothesis is that the rate of patients with an undetectable PSA is ≤ 40% after 6 cycles of treatment, while the alternate hypothesis is an undetectable PSA of > 60%; with one-sided α = 0.05, power = 0.80, and an assumed dropout rate of 10%, the required number of patients for an effective analysis is 47. Enrolment in the study commenced in May 2023.DiscussionThe multi-modal therapy based on treatment response may improve the prognosis of newly diagnosed mHSPC patients with oligometastases.Trial registrationThe study is registered with Clinical Trials.Gov (NCT05717582). Registered on 8th February 2023.