[177Lu]Lu-PSMA-617 was approved by the U.S. Food and Drug Administration for patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC). Since the time of regulatory approval, however, real-world data have been lacking. This study investigated the efficacy, safety, and outcome predictors of [177Lu]Lu-PSMA-617 at a major U.S. academic center. Methods: Patients with mCRPC who received [177Lu]Lu-PSMA-617 at the Johns Hopkins Hospital outside clinical trials were screened for inclusion. Patients who underwent [177Lu]Lu-PSMA-617 and had available outcome data were included in this study. Outcome data included prostate-specific antigen (PSA) response (≥50% decline), PSA progression-free survival (PFS), and overall survival (OS). Toxicity data were evaluated according to the Common Terminology Criteria for Adverse Events version 5.03. The study tested the association of baseline circulating tumor DNA mutational status in homologous recombination repair, PI3K alteration pathway, and aggressive-variant prostate cancer-associated genes with treatment outcome. Baseline PSMA PET/CT images were analyzed using SelectPSMA, an artificial intelligence algorithm, to predict treatment outcome. Associations with the observed treatment outcome were evaluated. Results: All 76 patients with PSMA-positive mCRPC who received [177Lu]Lu-PSMA-617 met the inclusion criteria. A PSA response was achieved in 30 of 74 (41%) patients. The median PSA PFS was 4.1 mo (95% CI, 2.0-6.2 mo), and the median OS was 13.7 mo (95% CI, 11.3-16.1 mo). Anemia of grade 3 or greater, thrombocytopenia, and neutropenia were observed in 9 (12%), 3 (4%), and 1 (1%), respectively, of 76 patients. Transient xerostomia was observed in 23 (28%) patients. The presence of aggressive-variant prostate cancer-associated genes was associated with a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P = 0.040). No other associations were observed between circulating tumor DNA mutational status and treatment outcomes. Eighteen of 71 (25%) patients classified by SelectPSMA as nonresponders had significantly lower rates of PSA response than patients classified as likely responders (6% vs. 51%; P < 0.001), a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P < 0.001), and a shorter OS (median, 6.3 vs. 14.5 mo; P = 0.046). Conclusion: [177Lu]Lu-PSMA-617 offered in a real-world setting after regulatory approval in the United States demonstrated antitumor activity and a favorable toxicity profile. Artificial-intelligence-based analysis of baseline PSMA PET/CT images may improve patient selection. Validation of these findings on larger cohorts is warranted.

The discovery and clinical development of radiolabeled small-molecule ligands targeting prostate-specific membrane antigen (PSMA) has had a profound influence on the field of nuclear medicine. Such agents have been successfully deployed for both imaging and therapeutic applications. In particular, PSMA radioligand therapy (PRLT) has been shown to be a life-prolonging therapy for men with metastatic, castration-resistant prostate cancer and has also brought nuclear medicine physicians and nuclear radiologists into the forefront of direct patient care. In this review, we will discuss the clinical study data regarding the efficacy and toxicities related to PRLT, outline the key personnel that any center offering PRLT should have, offer salient clinical examples, and provide an overview of future directions for PRLT. As PRLT continues to evolve as a treatment modality, it is paramount that nuclear medicine physicians and nuclear radiologists understand the clinical context, management implications, and practical aspects so as to best deliver high-value care to patients.

The discovery and clinical development of radiolabeled small-molecule ligands targeting prostate-specific membrane antigen (PSMA) has had a profound influence on the field of nuclear medicine. Such agents have been successfully deployed for both imaging and therapeutic applications. In particular, PSMA radioligand therapy (PRLT) has been shown to be a life-prolonging therapy for men with metastatic, castration-resistant prostate cancer and has also brought nuclear medicine physicians and nuclear radiologists into the forefront of direct patient care. In this review, we will discuss the clinical study data regarding the efficacy and toxicities related to PRLT, outline the key personnel that any center offering PRLT should have, offer salient clinical examples, and provide an overview of future directions for PRLT. As PRLT continues to evolve as a treatment modality, it is paramount that nuclear medicine physicians and nuclear radiologists understand the clinical context, management implications, and practical aspects so as to best deliver high-value care to patients.

BACKGROUND:The approval of the prostate-specific membrane antigen (PSMA)-targeted radio-ligand therapy [177Lu]Lu-PSMA-617 represents a shift toward precision medicine-based treatments for metastatic castration-resistant prostate cancer.OBJECTIVES:This review aims to provide practical advice and clinical considerations for working with [177Lu]Lu-PSMA-617; particularly, regarding the role of nurses in managing radiation safety, monitoring and reporting of adverse events, and counseling patients receiving this therapy.METHODS:Clinical data, protocols, and guidelines are summarized alongside real-world insights to provide practical recommendations for nurses caring for patients treated with [177Lu]Lu-PSMA-617.FINDINGS:Nurses coordinate safe care for patients receiving [177Lu]Lu-PSMA-617 by facilitating communication among physicians, managing logistic concerns, monitoring for adverse events related to treatment, providing education, and counseling patients and caregivers throughout treatment.

Background Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses. We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide. Methods We did this single-centre, open-label, phase 2, multicohort study in the USA. We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone. Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0-2, and did not have high-risk lesions for tumour flare (eg, > 5 sites of visceral disease or bone lesions with impending fracture). For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation. Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy. Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily. The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA 50) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing. The trial is registered with ClinicalTrials.gov, number NCT02090114. Findings Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT. Nine (30%; 95% CI 15-49; p<0.0001) of 30 patients achieved a PSA 50 to BAT. 29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33-71; p<0.0001) achieved a PSA(50) response. During BAT, the only grade 3-4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3-4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment. Interpretation BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge. Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between androgen and antiandrogen therapies in metastatic castration-resistant prostate cancer to maximise therapeutic benefit to patients.

236 Background: We documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e. BAT) [PMID: 25568070]. Since the adaptive increase in androgen receptor expression that follows chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with HS PC would also respond to BAT if given following a 6-month ADT lead-in. Methods: Men with asymptomatic HS PC and low metastatic burden (N = 20) (no visceral disease, ≤ 10 bone metastases, no lymph nodes > 5 cm short axis diameter) or non-metastatic biochemically recurrent disease (N = 13) were enrolled. Following 6-months of ADT, those with a PSA < 4 ng/ml went on to receive 2 cycles of BAT. A cycle of BAT was defined as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29 and 57 followed by ADT alone D 85-169. ADT was continued throughout the study to allow for rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA < 4 ng/ml after 2 cycles of BAT, with the study designed to reject a null rate of 40% at a one-sided alpha = 0.1. Secondary endpoints included quality of life (QOL) as measured by the SF-36, FACT-P, IIEF and IPSS surveys. Results: Twenty-nine of 33 patients received BAT following the ADT lead-in (1 withdrew consent, 3 had PSA > 4 ng/ml). The primary endpoint was met, with 17/29 men (59%, lower bound 90% confidence interval = 45%) having a PSA < 4 ng/ml after 2 cycles of BAT. Ten patients receiving BAT had RECIST evaluable disease, and 8 (80%) objective responses were observed (4 complete; 4 partial). Three patients progressed per RECIST criteria and 3 had unconfirmed progression on bone scan. Men treated with 6-months of ADT had improved QOL after the first cycle of BAT. The median improvement in SF-36, FACT-P, and IIEF total scores were 3.2 (range, -20 to 48; P = 0.21), 3.5 (range, -30 to 50; P = 0.04), and 10 (range, -4 to 59; P < 0.001) points, respectively. There was no change in total IPSS score (median change 0 [range, -9 to 8; P = 0.87]). Conclusions: BAT demonstrated preliminary efficacy in men with HS PC following 6-months of ADT. BAT may improve QOL in men that have received ADT. Clinical trial information: NCT01750398.

BACKGROUND:We have previously documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e., Bipolar Androgen Therapy; BAT). Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone-sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6-month ADT lead-in. METHODS:Asymptomatic HS PC patients with low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT. BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA <4 ng/ml after 18 months. Secondary endpoints included radiographic response and quality of life (QoL). RESULTS:Twenty-nine of 33 patients received BAT following the ADT lead-in. The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42-74%) having a PSA <4 ng/ml at 18 months. Ten patients receiving BAT had RECIST evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of ADT had improved QoL following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys. CONCLUSIONS:BAT demonstrated preliminary efficacy in men with HS PC following 6-month of ADT. BAT may improve QoL in men treated with ADT. Prostate 76:1218-1226, 2016. © 2016 Wiley Periodicals, Inc.

TPS5079 Background: Prostate cancer can progress despite androgen deprivation therapy through overexpression of the androgen receptor (AR) and expression of AR splice variants. Almost paradoxically, testosterone given to cancer cells in this state can cause growth inhibition. The AR is normally degraded during progression through the cell cycle, but androgen-bound AR is stabilized, thus arresting the cell cycle and inducing DNA strand breaks through interaction with topoisomerase-IIb. Clinically, supraphysiologic testosterone given to men with castration-resistant prostate cancer was found to be safe in a pilot clinical trial, producing responses and re-sensitizing patients to subsequent anti-androgen therapy. In this context, we designed a randomized phase II study comparing bipolar androgen therapy (BAT) to enzalutamide for patients who have experienced progression on abiraterone. Methods: In this multi-center randomized study, funded by a grant from the Department of Defense, eligible patients have asymptomatic metastatic castration-resistant prostate cancer that has radiographically or biochemically progressed after treatment with abiraterone. Patients are enzalutamide-naïve and have not received docetaxel for castration-resistant disease. Patients randomized to BAT will continue on androgen deprivation therapy and receive monthly intramuscular testosterone at the FDA-approved dose of 400mg. This dose produces initial supraphysiologic testosterone levels with return to castrate levels after one month. Patients randomized to enzalutamide will receive 160mg daily. Crossover is encouraged. The primary endpoint is radiographic progression-free survival (rPFS). The trial is powered to detect a 50% improvement in median rPFS in the BAT arm compared to the enzalutamide arm (expected to be ~6 months), with planned accrual of 90 patients in each arm. The arms will be stratified for time to progression on abiraterone. Secondary endpoints include PSA response rates, safety, and quality of life. Correlative studies include the effect of BAT on AR variant expression. Enrollment opened in February 2015. Clinical trial information: NCT02286921.

Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer. Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs). Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to chronic exposure to a low-testosterone environment. However, preclinical models suggest that AR overexpression represents a therapeutic liability that can be exploited via exposure to supraphysiologic testosterone to promote CRPC cell death. Preclinical data supported a pilot study in which 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg intramuscular; day 1 of 28) and etoposide (100 mg oral daily; days 1 to 14 of 28). After three cycles, those with a declining prostate-specific antigen (PSA) continued on intermittent testosterone therapy monotherapy. Castrating therapy was continued to suppress endogenous testosterone production, allowing for rapid cycling from supraphysiologic to near-castrate serum testosterone levels, a strategy termed bipolar androgen therapy (BAT). BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic responses (5 of 10 evaluable patients). Although all men showed eventual PSA progression, four men remained on BAT for ≥1 year. All patients (10 of 10) demonstrated PSA reductions upon receiving androgen-ablative therapies after BAT, suggesting that BAT may also restore sensitivity to ADTs. BAT shows promise as treatment for CRPC and should be further evaluated in larger trials.

45 Background: Prostate cancer (PC) cells become resistant to chronic castration via an adaptive increase in androgen receptor (AR) expression, a liability that can be exploited therapeutically. Mechanistically, supraphysiologic androgens can induce PC cell death through topoisomerase 2 (topo2) mediated double-strand DNA breaks and disruption of DNA relicensing due to persistence of AR at origins of replication during the cell cycle. Methods: We evaluated parenteral T in combination with the topo2 inhibitor E in men with CRPC and low metastatic burden (≤5 bone and <10 soft tissue metastases). To rapidly cycle from supraphysiologic (>1500 ng/dL) to near castrate T levels, men received intramuscular T cypionate 400 mg on day (D) 1 and oral E 100 mg D 1-14 of a 28 D cycle. After 3 cycles, men with declining PSA could continue T alone every 28 D. The primary endpoint was PSA response, defined as a PSA below baseline, after cycle 3. Secondary endpoints included objective response rates and safety. Results: Sixteen men enrolled of which 14 completed 3 cycles of T+E and were evaluable for response. 7/14 went on the T-only expansion stage. After 3 cycles, 6/14 men had a PSA response. 7 (50%) had a PSA response at any timepoint [4 (29%) had PSA declines ≥50%] (table). In men with RECIST-evaluable disease, 2 had progressive and 3 had stable disease (SD), 4 had partial (PR) and 1 had a complete response (CR). Median response duration was 248 D (range, 80 to 359 D). Post T, 10/12 men had a PSA decline to subsequent androgen ablative therapies. Most adverse events (AEs) were ≤grade 2 and considered effects of E. One man died from neutropenic sepsis before completing the 1st cycle. AEs possibly related to T included lower extremity edema (n=1), priapism (n=1) and asymptomatic pulmonary embolism (n=2). No one developed new pain on T. Conclusions: T with or without E demonstrated preliminary efficacy in patients with CRPC as manifested by PSA and objective responses. This regimen is generally safe. Cyclic T-based therapies warrant further study. Clinical trial information: NCT01084759. [Table: see text]

Purpose To find the maximum tolerated dose (MTD) of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors. Methods This was a Phase I study using cohort dose escalation of OSI-461 dosed orally twice daily in combination with mitoxantrone 12 mg/m 2 given on Day 1 of each 21-day cycle. Results OSI-461 dose was escalated to 1,000 mg po bid. One patient experienced a dose-limiting toxicity (DLT). Three patients discontinued the study due to adverse events (AE). Two patients (10%) had a partial response, and ten patients (50%) had stable disease as best response. Conclusion The combination of OSI-461 and mitoxantrone was well tolerated. Dose escalation was stopped because of toxicities in a concurrent Phase I trial. The response rate seen in patients with prostate cancer was comparable to response rates seen in trials of mitoxantrone and prednisone alone, and further studies of the combination of OSI-461 and mitoxantrone were not pursued.

BACKGROUND Gefitinib is an orally active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) with activity in non-small-cell lung cancer. The response to gefitinib is variable, possibly because of interindividual variation in the activity of cytochrome P450 3A (CYP3A), the principal enzyme that metabolizes gefitinib. We prospectively assessed the influence of CYP3A activity on gefitinib disposition and toxicity. METHODS Twenty-seven patients with advanced cancer were treated with daily oral gefitinib at 250 mg (n = 13) or 500 mg (n = 14) for 28 days. Concentration-time profiles of midazolam and geftinib were constructed based on measurement of their concentration in serial blood samples using high-performance liquid chromatography and mass spectroscopy. CYP3A activity was determined at baseline by assessment of midazolam apparent oral clearance. Pharmacokinetic studies were performed for a period of 28 days, and population modeling was performed using NONMEM software. A structural pharmacokinetic model was developed to describe the concentration-time profiles of unbound and total gefitinib plasma concentrations, and patient-specific covariates were added to the model to account for unexplained interindividual variability in pharmacokinetic parameters. Statistical tests were two-sided. RESULTS Gefitinib pharmacokinetics exhibited wide interindividual variability (interindividual variability on total and unbound gefitinib apparent oral clearance was 79% and 74%, respectively). Midazolam clearance (mean = 40 L/h, range = 10-111) was highly correlated with that of total and unbound gefitinib (R2 = .60 and R2 = .68, respectively) and with steady-state plasma trough concentrations of gefitinib (R2 = .58 and R2 = .60, respectively), and it accounted for approximately 40% of interindividual variability in gefitinib clearance in the pharmacokinetic model. Both total and unbound gefitinib steady-state plasma trough concentrations were associated with the development of diarrhea (P<.05), but not skin rash. At a dose of 250 mg gefitinib, 11 of 13 patients achieved steady-state plasma trough concentrations above the IC50 for inhibition of mutant EGFR in vitro (0.015 microM), but only one achieved a steady-state plasma trough concentration above the IC50 for inhibition of wild-type EGFR (0.1 microM). CONCLUSIONS As an in vivo phenotypic probe of CYP3A, midazolam oral clearance may have utility for prediction of gefitinib exposure and dose selection. A pharmacokinetic model incorporating this indicator of CYP3A activity has potential for optimization of treatment with gefitinib and other TK inhibitors that are metabolized in a similar manner.