PSMA Imaging Research Articles

Potential of Radiolabeled PSMA PET/CT or PET/MRI Diagnostic Procedures in Gliomas/Glioblastomas.

Background: Radiolabeled prostate-specific membrane antigen PSMA-based PET/CT or PET/MRI is a whole-body imaging technique currently performed for the detection of prostate cancer lesions. PSMA has been also demonstrated to be expressed by the neovasculature of many other solid tumors.Objective: The aim of this review is to evaluate the possible diagnostic role of radiolabeled PSMA PET/CT or PET/MRI in patients with gliomas and glioblastomas, by summarizing the available literature data.Methods: A comprehensive literature search of the PubMed/MEDLINE, Scopus, Embase and Cochrane library databases was conducted to find relevant published articles about the diagnostic performance of radiolabeled PSMA binding agents in PET/CT or PET/MRI imaging of patients with suspected gliomas or glioblastomas.Results: Seven case reports or case series and 3 studies enrolling more than 10 patients showed that gliomas and glioblastoma are PSMA-avid tumors.Conclusion: Radiolabeled PSMA imaging seems to be useful in analyzing glioma/glioblastoma. Further studies enrolling a wider population are needed to clarify the real clinical and diagnostic role of radiolabeled PSMA in this setting and its possible position in the diagnostic flow-chart.

Stereotactic body radiotherapy (SBRT) for the treatment of bone metastases in oligometastasised prostate cancer

Local radiation therapy of metastases in prostate cancer patients has become increasingly important in recent years. In order to improve the evaluation of the outcome, we have studied oligometastatic prostate cancer patients who were treated with stereotactic radiation therapy. 24 patients with a total of 30 bone metastases were included in the study. We examined the response to SBRT (biochemical and imaging), as well as progression-free survival and time to start of antihormonal therapy (aHT). The mean follow-up interval after completion of SBRT was 32.7 months (1.4 - 84 months). The SBRT was well tolerated, without acute or late adverse effects. In 16 patients, the PSA value decreased from a mean of 4.58 ng/mL (0.05 - 50.25 ng/mL) before SBRT to 1.19 ng/mL (0.01 - 8.85 ng/mL) after completion of SBRT. The mean biochemical progression-free survival of these patients was 17.6 months (0.7 - 85.0 months). Six patients received aHT, either before or during SBRT. In ten patients, the aHT was initiated after a mean interval of 20.6 months (1.8 - 85.0 months) after completion of the SBRT. Another six patients were not given any aHT during the whole period of observation. In 18 of 30 metastases, there was a decrease in PSMA expression within the area of SBRT in the PSMA-PET - in accordance with a partial functional response. In five patients, PSMA hyperexpression was unchanged; in 7 patients there was no PSMA imaging for follow up. In 17 patients, distant metastasis progression was diagnosed by imaging after a mean of 16.2 months (1.6 - 40.6 months). Three patients had a local recurrence in the prostatic fossa. SBRT of bone metastases in oligometastatic prostate carcinoma patients is an effective and well tolerated therapy and can help to achieve high local control in the area of the metastases as well as delay the start or the escalation of systemic therapy. Nevertheless, the high rate of progression of distant metastases shows how important correct patient selection is and that combination with aHT may be necessary.

PD54-03 SPECT IMAGING WITH TC99PSMA FOR PROSTATE CANCER AND ITʼS USE IN SALVAGE SURGERY

INTRODUCTION AND OBJECTIVE: PSMA-PET with either Ga68 or F18 has revolutionised the imaging of prostate cancer. SPECT imaging with Tc99-PSMA became commercially available later than PSMA-PET and uptake has been slower. Tc99-PSMA SPECT offers a much cheaper option than PSMA-PET, provides access to PSMA imaging where PET scanners are not available and allows PSMA radio guided surgery. Reliable identification of small or atypically placed pelvic nodes can be difficult at salvage surgery for recurrent prostate cancer. Tc99 injected into the penis is used for radio guided sentinel node dissection for penile cancer. In a similar, but chemically more challenging way, Tc99 bound to PSMA injected intravenously allows the possibility of radio-guided salvage node dissection to identify nodes with metastatic prostate cancer. The hope is that this will improve the likelihood of successful salvage nodal dissection, perhaps especially for small lesions. We describe our initial experience of this novel technique. METHODS: A prospective database of all patients undergoing Tc99 PSMA-SPECT either for staging, investigation of PSA recurrence or prior to salvage radio guided surgery at our regional hospital was kept. Munchen University PSMA I&S product was initially used. On average it required 90 minutes to create the Tc99-PSMA ligand complex. Following synthesis, a standard whole body SPECT was performed. Due to availability issues this was replaced by the Izotop PSMA ligand. This required only 20 minutes’ preparation time. There was no obvious difference in quality of imaging obtained between kits used. Stability of product and ligand to radiopharmaceutical binding has been excellent. Radio guided surgery is performed by injecting Tc99-PSMA prior to surgery. A SPECT image is then created localising the known (metastatic) disease. At surgery a hand held gamma probe is used to locate the "hot" node. After removal gamma readings are performed on the resected node to confirm presence of Tc99. RESULTS: 40 patients have undergone Tc99-PSMA SPECT imaging. Initial patients were chosen to ensure high probability of metastases to confirm suitability of SPECT imaging as a tool to image early prostate cancer metastases. SPECT imaging has identified metastatic disease including atypical sites in both patients presenting with initial disease and with PSA recurrence. 3 patients have undergone radio guided salvage surgery. The initial patient had salvage surgery with a handheld gamma probe to assist identification of the affected node on the same day as the injection. Significant background radioactivity in the urine limited the applicability of the technique. The gamma probe could however confirm the presence of Tc-PSMA in the resected node once removed from the body. The subsequent 2 patients underwent injection of Tc99-PSMA the day prior to surgery. This enabled a much more targeted approach with less background radioactivity and successful identification of the affected nodes in situ. Size of metastases was 2.5 mm, 3 and 4mm. In one patient successful node dissection for a 2.5 mm and a 4 mm seperate node was performed using radio guidance after a previous failed open salvage node dissection, which itself was post RALP with node dissection and post salvage radiotherapy. Nodes were deep to scar tissue and would not have been located without the gamma probe. CONCLUSIONS: Tc99-PSMA SPECT provides affordable PSMA imaging as an alternative to PET imaging. Both the Munich and Izotop product have been stable and produced high quality PSMA based images and allowed identification of atypical prostate cancer metastases. The Izotop product has a markedly quicker production time without loss of efficacy. In addition Tc99PSMA has allowed us to perform successful radio guided salvage node dissection in patients with small and usually atypically placed nodal metastases in recurrent disease. It is anticipated that this can also be used in men who present with small nodal oligo metastases at diagnosis and wish to have this treated. Source of Funding: The Waikato Urological research Trust

MP13-17 THE EFFECT OF STAGING WITH 68GA-PSMA PET/CT IMAGING ON CLINICAL DECISION FOR TREATMENT PROTOCOL OF HIGH RISK PROSTATE CANCER PATIENTS

INTRODUCTION AND OBJECTIVE: Staging in high risk prostate cancer patients (Gleason score >7, PSA >20 ng/mL, clinical stage T2c – 3a) with 68Ga-PSMA PET/CT is useful for detecting metastatic disease especially valuable for oligometastatic disease. It has shown to change the treatment protocol in patients with biochemical recurrence (BCR) however, there is still less data with the patients for recently diagnosed prostate cancer or staging. METHODS: Recently diagnosed prostate cancer patients suspected with metastatic disease, additionally patients with findings either Gleason score of higher than 7 or higher PSA values were included in our study. Fifty-seven patients with prostate cancer were scanned for staging. Between 3,6-5,5 mCi 68Ga-PSMA was injected. Patients were scanned 60 minutes after injection. Images were evaluated by two nuclear medicine specialists. Furthermore, two different urologists separately evaluated all patients for treatment protocol. First, the evaluation is done without PSMA PET/CT results and for second evaluation they have been given the results of the PSMA scans. RESULTS: Patient ages were between 36-86 years and mean PSA value was 152 (4,1-1957 ng/ml). All Gleason scores were higher than 7, except seven patients who had PSA values of >20ng/ml. 45% of the patients had positive findings for lymph node metastases; 28% of the patients had distant metastasis. Between 41% and 50% of changing rates were calculated for the treatment protocols after PSMA scan results. CONCLUSIONS: Several studies have already revealed the use of 68Ga-PSMA PET/CT in prostate cancer with the suspect of BCR. However, there is still debate about the use of PSMA imaging in staging prostate cancer patients. The patients in our series showed the contribution of PSMA imaging is not negligible with the change rates of 41-50% in treatment protocol. However further discussion with higher patient numbers is needed for the cost-effectiveness. Source of Funding: The authors declare no source of funding.

FDG and PSMA PET in metastatic castration-resistant prostate cancer (mCRPC).

23 Background: We hypothesized 18F-DCFPyL (PSMA-based tracer) and/ or 18F-FDG (glucose metabolism-based tracer) PET/CT might provide different/complementary molecular imaging information in men with mCRPC treated with abiraterone (A) or enzalutamide (E). Methods: In this prospective cohort study (MISTER trial) mCRPC patients (pts) had conventional imaging and both PSMA and FDG PET/CT prior to standard treatment with A or E, repeated after ~10 weeks on treatment. The main objective was to compare changes in PET/CT findings with conventional imaging. Median of PET maximum standardized uptake value (SUVmax) was measured across all PET avid disease sites and change in SUVmax was evaluated in the 5 hottest sites per patient. Review of PET/CT was performed by 3 experts based on consensus. Results: 36 men were enrolled between 2/2017-12/2018, of whom 28 had treatment and followup imaging. To date, 13 cases have been reviewed: mean age 71.2 years, 7 (53.9%) were ECOG=0, median duration since diagnosis of initial cancer 7.5 months and 8 (61.5%) were stage II/III. PSMA detected more skeletal metastases, positive nodes and non-skeletal, non-nodal metastases in 5/5/3 (39%/39%/23%) men, while FDG detected more non-skeletal, non-nodal metastases in 1 man. Following treatment, new lesions were seen in 3 men on both PSMA and FDG, 3 with PSMA only, and 1 with FDG only. 12 men had baseline FDG-avid disease with median SUVmax 6.5 pre-treatment and 3.8 following therapy (all men had lower SUVmax post-treatment). All 13 men had PSMA-avid disease with median SUVmax 17.6 at baseline and 18.7 post-therapy. Following treatment, 8/12 men (67%) had SUV declines ≥30% (2 had new lesions), 4 had declines of 0-30% (2 had new lesions) using FDG; at followup, 1/13 men had PSMA SUVmax declines ≥30% or more, 6 had declines of 0-30% (2 had new lesions), 5 had SUV increases of 0-30% (4 had new lesions) and 1 had >30% increase. Conclusions: In early analyses, PSMA identified more disease burden in mCRPC pts and was more avid than FDG. SUVmax for FDG declined following treatment in all men, while PSMA changes were heterogeneous. Potential prognostic value of early PSMA and FDG imaging changes on clinical outcomes will be correlated with conventional imaging along with review of remaining cases. Clinical trial information: NCT02813226.

Deep Neural Network for Automatic Characterization of Lesions on 68Ga-PSMA PET/CT Images.

The emerging PSMA-targeted radionuclide therapy provides an effective method for the treatment of advanced metastatic prostate cancer. To optimize the therapeutic effect and maximize the theranostic benefit, there is a need to identify and quantify target lesions prior to treatment. However, this is extremely challenging considering that a high number of lesions of heterogeneous size and uptake may distribute in a variety of anatomical context with different backgrounds. This study proposes an end-to-end deep neural network to characterize the prostate cancer lesions on PSMA imaging automatically. A 68Ga-PSMA-11 PET/CT image dataset including 71 patients with metastatic prostate cancer was collected from three medical centres for training and evaluating the proposed network. For proof-of-concept, we focus on the detection of bone and lymph node lesions in the pelvic area suggestive for metastases of prostate cancer. The preliminary test on pelvic area confirms the potential of deep learning methods. Increasing the amount of training data may further enhance the performance of the proposed deep learning method.

Phase I/II dose-escalation trial of fractionated dose 177Lu-J591 plus 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC).

TPS339 Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. Prior studies of beta-emitting radiolabeled anti-PSMA antibody J591 demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable dose-limiting myelosuppression. Recent prospective trials have shown efficacy and safety of 177Lu-PSMA-617 in mCRPC. Studies demonstrate different binding sites of J591 and PSMA-617 and co-administration leads to non-competitive additive binding and delivery of payloads to PSMA+ cells. As the pharmacokinetics and biodistribution of the 2 agents is mostly non-overlapping (other than tumor) and given our prior dose-response data, we hypothesize that delivery of the combination will yield higher tumor delivery with less off-target toxicity (i.e. better responses without increased toxicity). Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) with metastatic disease on CT/MRI or bone scan without limit of # prior therapies (excluding bone-targeted beta-emitting radioisotopes) provided adequate organ function will be enrolled. Pre-treatment 88Ga-PSMA-11 will be performed, but results are not used for eligibility. Treatment includes fractionated 177Lu-J591 at a fixed moderate dose with escalating doses of 177Lu-PSMA-617 (7.4 – 18.5 GBq per cycle, fractionated D1 and D15) in a 3+3 dose-escalation study. Dose-limiting toxicity (DLT) is defined as attributable grade > 3 heme toxicity or grade > 2 non-heme toxicity. Following determination of recommended phase 2 dose (RP2D), the phase 2 portion will enroll in a 2-stage design. Primary endpoints: DLT and RP2D (ph 1) and PSA decline proportion (ph 2). Secondary endpoints include toxicity, radiographic response, PFS, rPFS, OS, CTC count changes. Correlatives include baseline/follow up PSMA imaging, whole body distribution of 177Lu, tissue and circulating genomic assessment, immunologic assessment, and patient reported outcomes (FACT-P and BPI-SF). Clinical trial information: NCT03545165.

517 - Pitfalls of PSMA imaging for nodal recurrences after radical prostatectomy: Comparison of PET/CT results with histopathology and PSMA immunostaining

517 - Pitfalls of PSMA imaging for nodal recurrences after radical prostatectomy: Comparison of PET/CT results with histopathology and PSMA immunostaining

Clinicopathological predictors of positive 68Ga-PSMA-11 PET/CT in PSA-only recurrence of localized prostate cancer following definitive therapy.

To demonstrate the effect of clinicopathological factors on 68Ga-PSMA-11 PET/CT positivity at the time of biochemical recurrence (BCR) of localized prostate cancer (PCa) following definitive therapy. We retrospectively reviewed our institutional database for PCa patients who had BCR and subsequently underwent 68Ga-PSMA-11 PET/CT between April 2014 and February 2018. A total of 51 patients who were metastasis-free before PSMA imaging and previously treated with definitive therapy (radical prostatectomy or external beam radiotherapy) for localized disease (pT1c-T3b pN0-1 cM0) were included. 37 out of 51 patients (72.5%) had positive 68Ga-PSMA-11 PET/CT scans. Age at diagnosis, Gleason score (GS), D'Amico risk status of PCa, initial PSA level before treatment and PSA doubling time were not associated with PSMA positivity. Pre-scan PSA levels of > 0.2ng/ml and PSA velocity of ≥ 1ng/ml/year were significantly associated with increased PSMA positivity, whereas history of androgen deprivation therapy showed a trend towards significance. The optimal cutoffs for distinguishing between positive and negative scans were ≥ 0.71ng/ml for pre-scan PSA and ≥ 1.22ng/ml/yr for PSA velocity. In multivariable analysis, log pre-scan PSA and pre-scan PSA level > 0.2ng/ml remained significant predictors for PSMA positivity, whereas the association of PSA velocity and of ADT was lost. In BCR of localized PCa following definitive therapy, pre-scan PSA was strongly associated with positive 68Ga-PSMA-11 scan, even at PSA levels ranging from 0.2 to 1.0ng/ml. Therefore, clinical and pathological predictors of positive 68Ga-PSMA-11 PET/CT in PSA-only recurrence of localized prostate cancer need to be further elucidated.

Phase I dose-escalation study of 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC).

TPS399 Background: PC is a radiosensitive disease. PSMA is overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of beta-emitting radiolabeled anti-PSMA monoclonal antibody (mAb) J591 have demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable, reversible dose-limiting myelosuppression. Alpha emitters are significantly more potent with a shorter range than beta emitters. Though there is no direct tumor-targeting, the bone-targeting alpha emitter Ra223 is approved. Anecdotal reports of PSMA small molecule targeted alpha emitters have hinted at efficacy but are limited by xerostomia and in mouse models may lead to long-term renal damage. Intact mAb J591 has comparatively no to minimal distribution in salivary glands and kidneys. Preclinical studies demonstrated purity, immunoreactivity, and stability with efficacy in a xenograft model [AACR 2017]. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies (excluding beta-emitting bone-targeted radioisotopes) provided adequate organ function will undergo imaging with 68Ga-PSMA-11 PET/CT followed by a single dose of 225Ac-J591. Single-subject cohorts will be enrolled until grade > 1 attributable toxicity, then transition to 3+3 design. Cohort 1 = 13.3 KBq/kg with planned escalation up to 93.3 KBq/kg of 225Ac with fixed 20 mg J591. Dose-limiting toxicity (DLT) is defined as attributable grade 4 heme toxicity or grade 3/4 non-heme toxicity. Planned cohort expansion will occur at recommended phase 2 dose (RP2D) in a 2-stage design. The primary endpoint is determination of DLT and RP2D. Secondary endpoints include toxicity, PSA decline rate, RECIST response, PFS, rPFS, OS, and patient reported outcomes (FACT-P and BPI-SF). Correlatives include baseline/follow up PSMA imaging, CTC count (CellSearch) changes, tissue and circulating genomic assessment, and immune studies. Enrollment began in October, 2017. Clinical trial information: NCT03276572.

816P - 68Ga-PSMA-PET/CT as a changing practice tool in biochemically recurrent prostate cancer

Background: PSMA-PET/CT have demonstrated interesting results in the detection of loco-regional and distant disease in prostate cancer patients with biochemical relapse. Even with low levels of PSA, PSMA imaging is able to identify metastatic lesions, being a possible tool for tailoring treatment decisions. This study aims to describe the use of PSMA-PET/CT in the daily practice and its clinical impact in the management of prostate cancer patients who have rising PSA after curative treatment. Methods: We performed a retrospective analysis in 29 localized prostate cancer patients of three private Brazilian cancer institutions who underwent PSMA-PET/CT for rising PSA after treatment with curative intent. The clinical impact of PSMA-PET/CT was evaluated by whether the assistant physician changed or not the treatment strategy based solely on PSMA results. In addition, modifications related to local (salvage radiotherapy [SRT], salvage lymphadenectomy [SL]) and systemic (antiandrogen deprivation therapy [ADT], chemotherapy [chemo]) treatment were described. Results: In total, 29 patients were enrolled. Twenty-seven (93%) had undergone radical prostatectomy, and 2 (7%) radiotherapy as the local curative treatment. Sixteen cases (55%) had not received any radiotherapy previously. The mean Gleason score, PSA level and PSADT at time of the examination were 8, 4.2 (0,05-41) ng/ml and 4.4 (0.4-27) months, respectively. PSMA-PET/CT detected at least one suspicious lesion for prostate cancer in 21/29 (58%) patients. Overall, 15/29 (51%) patients had their treatment strategy changed due to results in PSMA imaging. In only 3/29 (10%) the modifications were related exclusively to systemic protocols (1 avoided ADT, 1 added ADT and, 1 added chemo). Whereas in the 12/29 (41%) remaining cases, treatment strategy change involved local treatment. Of these 12 with a local treatment change, 7 added (6 SL, 1 SRT) and 5 avoided (5 SRT) local therapies. Conclusions: Half of the patients with biochemical relapse that underwent PSMA-PET/CT had their treatment protocol changed, most changes related to local treatment. Although the role of PSMA imaging is not clearly defined, PSMA-PET/CT has been used as a practice changing tool in the daily practice. Legal entity responsible for the study: Instituto COI Funding: None Disclosure: All authors have declared no conflicts of interest.

The phytological future of prostate cancer staging: PSMA-PET and the dandelion theory.

PSMA-PET is changing how we stage prostate cancer, both in the primary setting and with relapse after treatment. It allows us to identify lesions in the bones and lymph nodes that were not previously visible on conventional imaging with bone scan and CT/MRI. In this Special Report we review the 'state of the art' for PSMA imaging and discuss the implications for treatment decisions in prostate cancer. We liken early high risk or metastatic prostate to a common phytological problem: the dandelion. In this analogous situation, we consider the additional evidence needed for us to start plucking out the original dandelion and for us to focus attention on killing the seeded weeds that are identifiable elsewhere in the lawn.

Phase I dose-escalation study of fractionated-dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC).

TPS5093 Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of radiolabeled anti-PSMA antibody J591 revealed 1) targeting and safety [Bander 2003]; 2) safety and prelim efficacy [Milowsky 2004, Bander 2005]; 3) efficacy and initial dose-response [Tagawa 2013]; 4) dose-fractionation allows higher doses, ability to combine with docetaxel, confirmation of dose-response (PSA and overall survival) [ASCO 2010, 2014, 2016]; 5) predictable, reversible myelosuppression is dose-limiting [Tagawa 2013]. Small molecule PSMA inhibitor ligands can be successfully radiolabeled and are widely used for imaging and treatment in Europe. 177Lu-PSMA-617 is the most commonly used, but experience is mostly anecdotal/retrospective and no formal dose-escalation studies have been performed. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function will undergo imaging with 68Ga-PSMA-HBED-CC PET/CT followed by escalating fractionated doses of 177Lu-PSMA-617. Cohort 1 = 3.7 GBq x2 two weeks apart up to 11.1 GBq x2 in a 3+3 dose-escalation study. Dose-limiting toxicity (DLT) is defined as attributable grade 4 heme toxicity or grade 3/4 non-heme toxicity. Planned cohort expansion will occur at recommended phase 2 dose (RP2D) in a 2-stage design. The primary endpoint is determination of DLT and RP2D. Secondary endpoints include toxicity, PSA decline rate, RECIST response, PFS, rPFS, OS. Correlatives include baseline/follow up PSMA imaging, whole body distribution of 177Lu-PSMA-617, CTC count (CellSearch) changes, tissue and circulating genomic assessment of DNA repair pathways, patient reported outcomes (FACT-P and BPI-SF). Clinical trial information: NCT03042468.

Patterns of failure on Ga PSMA (GaPSMA) and F18 FDG (FDG) PET CT in a prospective phase 2 trial of 177Lu DKFZ PSMA 617 (LuPSMA) in men with castrate resistant metastatic prostate cancer (mCRPC).

2562 Background: LuPSMA is emerging as an effective therapy in mCRPC, with retrospective series reporting high PSA response rates in men undergoing treatment (tx). However, not all men have prolonged tx responses. We report the prospective imaging (GaPSMA/FDG) and PSA response of men who progress biochemically during LuPSMA tx to gain information on characteristics of failure patterns, to determine optimal future tx strategies. Methods: Men with mCRPC, who had failed androgen blockade, failed/ ineligible/refused chemotherapy, with GaPSMA positive disease were enrolled in a prospective phase 2 trial. All men underwent LuPSMA therapy 6-8Gbq, 4 doses at 6 weekly intervals. Imaging with FDG, GaPSMA, bone scan and CT scans was at screening, at subsequent PSA rise, or 3 months post completion of 4 cycles of therapy. Results: 14 men met eligibility criteria and enrolled. 4/14 (28%) men had progressive disease (no PSA response). 10/14 (72%) PSA reduced by a mean 56% .Overall 9/14 (64%) men had >30% decline in PSA, and 5/15(36%) >50% reduction in PSA. 7/15 men were reimaged with GaPSMA, FDG at biochemical failure or 3/12 post tx completion. Imaging revealed 4 distinct patterns (P) of progression. Conclusions: PSMA acts as both target for radionuclide therapy and biomarker for effective tx response. PSMA and FDG imaging at PSA failure following or during LU PSMA therapy identifies phenotypic patterns of failure that have implications for determining next best tx options in men with mCRPC. [Table: see text]

The CHAPPP study: Changing care with PSMA-PET for prostate cancer—A retrospective study of the role of PSMA imaging in altering treatment pathways.

13 Background: The low sensitivity of standard imaging (SI) techniques in detecting metastases (Ms) may lead to unnecessary local treatment for patients (Pts) with newly diagnosed or recurrent prostate cancer (PC). Ga-68-PSMA (Prostate Specific Membrane Antigen)-PET-CT is a novel imaging technique with increased sensitivity in detection of PC especially at low PSA values and may change the decision to pursue primary local or salvage treatment. This study quantified changes in definitive local treatment secondary to occult Ms detected on Ga-68-PSMA not visualized on SI. Methods: A retrospective study was performed of 509 consecutive PSMA scans (and 481 Pts) at our tertiary cancer centre, the Royal Brisbane and Women’s Hospital between Sept 2014 and Dec 2015. PSMA imaging was compared with a CT scan and bone scan to determine whether PSMA results altered the decision to pursue local treatment. Results: 81 (16%) Pts had PSMA-PET-CT scan and no Ms on SI, 40 prior to definitive local treatment and 41 as work up for recurrence. 9/40 Pts (23%) undergoing primary work-up had PSMA-identified Ms not visible on SI and altered these patients treatment pathway (mean PSA 20.5 ng/mL). Because of PSMA-diagnosed Ms, 3 did not receive local treatment. 4 had pelvic nodal involvement and received definitive radiotherapy (RT) including nodal fields. 2 Pts proceeded to radical prostatectomy with the addition of lymph node dissection. 41 Pts investigated for recurrence following local treatment had SI for comparison, (mean PSA 4.7, range 0.11 – 35 ng/mL). 11/41 (27%) were found to have distant or nodal Ms not visualized on SI. 7/11 with prior surgery did not proceed to salvage RT and the remaining Pts who had Ms were referred for an earlier medical oncology opinion. In total 20/81 (25%) of Pts had a direct change in treatment due to the additional information conferred by PSMA imaging. Conclusions: PSMA is more sensitive in the detection of prostate cancer Ms for patients being evaluated for primary treatment or looking for recurrence following local treatment. These results show clinically meaningful changes in management with avoidance of local treatment because of enhanced detection of metastases.

The CHAPPP study: Changing care with PSMA-PET for prostate cancer—A retrospective study of the role of PSMA imaging in altering treatment pathways.

The CHAPPP study: Changing care with PSMA-PET for prostate cancer—A retrospective study of the role of PSMA imaging in altering treatment pathways.

SU-E-I-82: PET Radiopharmaceuticals for Prostate Cancer Imaging: A Review

Purpose: The aim of this work was to review new and clinical practice PET radiopharmaceuticals for prostate cancer imaging. Methods: PET radiopharmaceuticals were reviewed on the main databases. Availability, dosimetry, accuracy and limitations were considered. Results: The following radioisotopes with respective physical half-life and mean positron energy were found: {sup 18}F (109,7 min, 249,8 keV), {sup 89}Zr (78,4 hs, 395,5 keV), {sup 11}C (20,4 min, 385,7 keV) and {sup 68}Ga (67,8 min, 836 keV). {sup 68}Ga was the only one not produced by cyclotron. Radiopharmaceuticals uptake by glucose metabolism ({sup 18}F-FDG), lipogenesis ({sup 11}C-Choline and {sup 11}C-Acetate), amino acid transport (Anti-{sup 18}F-FACBC), bone matrix ({sup 18}F-NaF), prostatespecific membrane antigen ({sup 68}Ga-PSMA and {sup 89}Zr-J591), CXCR receptors ({sup 89}Ga-Pentixafor), adrenal receptors ({sup 18}F-FDHT) and gastrin release peptide receptor (bombesin analogue). Most of radiopharmaceuticals are urinary excretion, so bladder is the critical organ. 11C-choline (pancreas), Anti-{sup 18}FFACBC (liver) and {sup 18}F-FBDC (stomach wall) are the exception. Higher effective dose was seen {sup 18}F-NaF (27 μSv/MBq) while the lowest was {sup 11}CAcetate (3,5 μSv/MBq). Conclusion: Even though {sup 18}F-FDG has a large availability its high urinary excretion and poor uptake to slow growing disease offers weak results for prostate cancer. Better accuracy ismore » obtained when {sup 18}F-NaF is used for bone metastatic investigation although physicians tend to choose bone scintigraphy probably due to its cost and practice. Many guidelines in oncology consider {sup 11}C or {sup 18}F labeled with Choline the gold standard for biochemical relapse after radical treatment. Local, lymph node and distant metastatic relapse can be evaluated at same time with this radiopharmaceutical. There is no consensus over bigger urinary excretion for {sup 18}F labeling. Anti-{sup 18}F-FACBC, {sup 68}Ga-PSMA and {sup 68}Ga-Pentixafor are demonstrating good results but more researches are needed. While PSMA imaging seems to be independent of PSA level, one choline limitation, anti-{sup 18}F-FACBC adds value because imaging any disease stage. {sup 68}Ga-Petixafor is being tested as theranostics marker integrating molecular image and therapy.« less

Phase II Study of Lutetium-177–Labeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Metastatic Castration-Resistant Prostate Cancer

To assess the efficacy of a single infusion of radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (lutetium-177; (177)Lu) by prostate-specific antigen (PSA) decline, measurable disease response, and survival. In this dual-center phase II study, two cohorts with progressive metastatic castration-resistant prostate cancer received one dose of (177)Lu-J591 (15 patients at 65 mCi/m(2), 17 at 70 mCi/m(2)) with radionuclide imaging. Expansion cohort (n = 15) received 70 mCi/m(2) to verify response rate and examine biomarkers. Forty-seven patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received (177)Lu-J591. A total of 10.6% experienced ≥50% decline in PSA, 36.2% experienced ≥30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity, with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. A total of 25.5% experienced grade 4 neutropenia, with one episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m(2)) resulted in more 30% PSA declines (46.9% vs. 13.3%, P = 0.048) and longer survival (21.8 vs. 11.9 months, P = 0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious nonhematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond. A single dose of (177)Lu-J591 was well tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose response. Imaging biomarkers seem promising.

Phase II trial of 177lutetium radiolabeled anti-PSMA antibody J591 (177Lu-J591) for metastatic castrate-resistant prostate cancer (metCRPC): Survival update and expansion cohort with biomarkers.

121 Background: A phase II trial in men with progressive metCRPC receiving a single dose of 177Lu-J591 at 65 mCi/m2 (15 pts) or 70 mCi/m2 (phase I MTD, 17 pts) was performed without selection for PSMA expression, suggesting a larger than expected dose-response (13 vs 47% >30% PSA decline respectively), leading to an expansion cohort to validate the response rate at 70 mCi/m2. Methods: Endpoints: to validate the PSA and/or measurable disease response at 70 mCi/m2, evaluate circulating tumor cell counts (CellSearch) and pre-treatment PSMA imaging with 111In-J591 in the expansion cohort, and examine overall survival (OS) for all pts. Results: 15 additional pts were treated. Expansion cohort demographics were similar to the initial cohorts, and PSA responses and toxicity were similar to the initial cohort treated at 70 mCi/m2 (see Table), with myelotoxicity improving in all following nadir at 1 month. More PSA declines and longer OS were seen at 70 mCi/m2. 12 of 15 pts had baseline and follow up CTC counts at 4-6 weeks: 66.7% had >50% decline and 25% were unchanged at 0 or 1 (one declined 27%). Although 93.3% had accurate targeting (imaging) of known sites of disease, as seen in initial analysis, a trend for fewer > 30% PSA declines was seen with less intense PSMA imaging. Conclusions: Single dose 177Lu-J591 at70 mCi/m2 was generally well tolerated, with predictable, reversible myelosuppression, and demonstrates anti-tumor activity in pts with progressive metCRPC. A dose-response relationship was confirmed for both toxicity and activity, with improved response and OS at 70 mCi/m2. CTC declines are demonstrated. Selection of pts based upon non-invasive testing (PSMA imaging) may improve the therapeutic profile. Clinical trial information: NCT00195039. [Table: see text]

Abstract B207: Prostate specific membrane antigen is a diagnostic marker of response to allosteric androgen receptor inhibition

Abstract Molecular imaging in oncology aims to complement the growing repertoire of chemotherapies with noninvasive diagnostic tools to measure pharmacodynamics and improve predictions of disease response. In prostate cancer, several chemotherapeutic strategies have been developed to inhibit androgen receptor (AR) function, and currently show promise in treating advanced, castration resistant disease. Among these, competitive inhibitors of steroid agonist/receptor interactions have been effectively staged with fluorine-18-fluoro-5α-dihydrotestosterone, an AR agonist compatible with quantitative PET imaging. However, some allosteric inhibitors of AR do not impact agonist/receptor interaction (or AR stability) and currently cannot be evaluated with a quantitative imaging technology. We address this problem here by presenting evidence that prostate specific membrane antigen is a diagnostic marker of allosteric AR inhibition. In culture or in xenograft models of LNCaP, 22Rv1, LAPC4, and VCaP, PSMA is repressed by androgen treatment. Ablation of AR with siRNA inhibits the hormone-mediated suppression of PSMA, directly implicating AR in the mechanism. We further show that PSMA suppression is antagonized by several competitive and allosteric AR inhibitors. Finally, we conducted a pilot study with 22Rv1 xenografts to demonstrate that 64Cu-DOTA-J591, a monoclonal antibody designed for clinical PET imaging of PSMA, quantitatively detects hormone-mediated PSMA suppression. Collectively, these results promote the use of PSMA imaging reagents in the clinic to stage allosteric AR inhibitors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B207.