Safety and Efficacy of BIND-014, a Docetaxel Nanoparticle Targeting Prostate-Specific Membrane Antigen for Patients With Metastatic Castration-Resistant Prostate Cancer

Key Points

Questions

What is the safety and efficacy of BIND-014, a docetaxel-containing nanoparticle targeting prostate-specific membrane antigen (PSMA), in metastatic castration-resistant prostate cancer, and does PSMA expression on circulating tumor cells decrease with treatment?

Findings

In this phase 2 clinical trial of 42 chemotherapy-naive patients receiving BIND-014 therapy for metastatic castration-resistant prostate cancer, the median radiographic progression-free survival was 9.9 months. The most common adverse events were fatigue. nausea, and diarrhea.

Meaning

Tumor cell death was associated with PSMA expression on circulating tumor cells, which, if validated, could serve as a pharmacodynamic response measure and help select patients with metastatic castration-resistant prostate cancer who are most likely to benefit from PSMA-directed treatment.

Abstract

Importance

Preferential delivery of docetaxel to tumors by prostate-specific membrane antigen (PSMA)–targeted nanoparticles is clinically effective, and the selective reduction of PSMA-positive circulating tumor cells (CTCs) after treatment has implications for patient selection and disease monitoring.

Objective

To determine the safety and efficacy of BIND-014, a PSMA-directed docetaxel-containing nanoparticle, in patients with metastatic castration-resistant prostate cancer (mCRPC).

Design, Setting, and Participants

A multicenter open-label, phase 2 clinical trial of 42 chemotherapy-naive patients with progressing mCRPC after treatment with abiraterone acetate and/or enzalutamide was conducted from June 24, 2013, to June 10, 2016.

Intervention

Treatment with BIND-014 at a dosage of 60 mg/m² was given intravenously on day 1 of 21-day cycles in combination with prednisone until disease progression or unacceptable toxic effects occurred.

Main Outcomes and Measures

The primary end point was radiographic progression-free survival according to Prostate Cancer Working Group 2 recommendations and Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included prostate-specific antigen (PSA) response (≥50% reduction from baseline) and changes in CTC number (from ≥5 to <5 cells per 7.5 mL of blood) (CellSearch). Changes in CTC number based on PSMA expression levels on CTCs were also evaluated (Epic Sciences).

Results

Among the 42 patients (81% white), the median age was 66 (range, 50-85) years, and median number of doses received was 6 (range, 1-21). A PSA response was observed in 12 of 40 patients (30%; 95% CI, 18%-45%), measurable disease response in 6 of 19 (32% [95% CI, 15%-54%]), and CTC conversions in 13 of 26 (50%; 95% CI, 32%-68%). Median radiographic progression-free survival was 9.9 (95% CI, 7.1-12.6) months. With use of the Epic Sciences non-EPCAM-based CTC detection platform, CTCs were detected in 16 of 18 patients (89%); 11 of 18 (61%) had CTCs with PSMA expression above the analytical threshold level (PSMA positive) at baseline (range, 0.4-72.4 CTCs/mL). After treatment, PSMA-positive CTCs were preferentially reduced. Treatment-related adverse events included grade 1 or 2 fatigue (29 of 42 patients [69%]), nausea (23 [55%]), neuropathy (14 [33%]), and neutropenic fever (1 [2%]).

Conclusions and Relevance

These findings suggest that treatment with BIND-014 is active and well tolerated in patients with chemotherapy-naive mCRPC. Antitumor activity may be related to PSMA expression levels on CTCs, which suggests that patients who are likely to benefit from this treatment can be identified before treatment is initiated.

Trial Registration

ClinicalTrials.gov Identifier: NCT01812746

This phase 2 clinical trial investigates the safety and efficacy of BIND-014, a docetaxel-containing nanoparticle targeting prostate-specific membrane antigen, for treating patients with metastatic castration-resistant prostate cancer.

Introduction

Prostate-specific membrane antigen (PSMA) is a cell surface protein that is present on most prostate cancers and the neovasculature of many other malignanct neoplasms but not on healthy tissue vasculature.^1,2 Expression of PSMA on the surface of prostate cancer cells and the rapid internalization of PSMA-binding therapeutic agents can be exploited to preferentially deliver radiopharmaceuticals, antibody-drug conjugates, and vaccines to tumor, in some cases guided by PSMA-directed positron emission tomography in a theranostic approach.^3,4,5,6 More recently, PSMA expression has been evaluated on circulating tumor cells (CTCs) for diagnostic purposes and to assess treatment effects.^7,8

A combination of docetaxel and prednisone has been the first-line, standard-of-care cytotoxic therapy for metastatic castration-resistant prostate cancer (mCRPC) since 2004, following the demonstration of a survival benefit in 2 pivotal phase 3 trials^9,10 and, more recently, in combination with androgen deprivation therapy (ADT) without prednisone for castration-sensitive disease based on the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) and Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial results.^11,12 In trials among patients with mCRPC conducted before the abiraterone/enzalutamide era, docetaxel given every 3 weeks had a modest advantage over mitoxantrone, with approximately 18.6% and 13.5% of patients alive at 3 years after trial treatment initiation, respectively.¹³ In more recent trials initiated in the metastatic castration-sensitive setting, the degree of survival benefit offered by adding 6 cycles of docetaxel to ADT compared with ADT alone is much higher, with a median overall survival of 57.6 (95% CI, 52.0-36.9) vs 47.2 (95% CI, 41.8-52.8) months; in the subset of patients with a high-volume burden of disease, a greater discrepancy was reported (median survival, 51.2 [95% CI, 45.2-58.1] vs 34.4 [95% CI, 30.1-42.1] months).¹⁴

Limitations to docetaxel use include the recognized toxic effects of a cytotoxic taxane, including myelosuppression, fatigue, and peripheral neuropathy.^9,10,11 Improving the therapeutic index and potentially lowering the toxicity of docetaxel by selective delivery of the drug to tumor relative to normal tissues is a critical unmet need. One method of enhancing drug delivery is through targeted nanoparticle technologies that rely on the enhanced permeability and retention effect of the lipid bilayer to exploit unique differences in tumor cells relative to normal cells. BIND-014 is a docetaxel-encapsulating nanoparticle and a hydrophilic polyethylene glycol corona decorated with small-molecule PSMA-targeting ligands. The modified nanoparticle is enriched in the tumor microenvironment and can be internalized on binding to a PSMA-expressing cell, enabling the preferential delivery of docetaxel to the tumor.¹⁵

Preclinical studies in xenograft models of prostate, breast, and non–small cell lung cancer showed increased intratumoral docetaxel concentrations, increased antitumor activity, and a lower volume of distribution and clearance compared with conventional docetaxel.¹⁶ A phase 1 clinical trial of BIND-014 in multiple solid tumors, which included 2 patients with mCRPC, established safety and defined a dosage of 60 mg/m² every 3 weeks for phase 2 study.¹⁵ Here, we report the results of a phase 2 clinical trial among patients with chemotherapy-naive mCRPC. Outcomes were assessed according to Prostate Cancer Working Group 2 (PCWG2)¹⁷ recommendations along with changes in CTC number (using CellSearch; Menarini Silicon Biosystems) and intrapatient changes in CTC subpopulation concentrations based on PSMA expression levels (measured using the Epic Sciences platform).

Methods

Patients

The trial was conducted from June 24, 2013, to June 10, 2016. Eligibility criteria included having mCRPC that was determined to be progressing on the basis of changes in prostate-specific antigen (PSA) or imaging as defined by PCWG2 guidelines. Patients may have experienced disease progression while receiving treatment with androgen receptor (AR)–targeted or AR axis–targeted agents (eg, abiraterone acetate and/or enzalutamide), whereas those patients treated with bicalutamide had to have cases that failed to respond to antiandrogen withdrawal. Earlier chemotherapy (for either castration-sensitive or castration-resistant disease) was not permitted. Patients were treated at 1 of 8 institutions (Memorial Sloan Kettering Cancer Center, New York, New York; Cleveland Clinic, Cleveland, Ohio; University of North Carolina at Chapel Hill; University of California, San Francisco; University of Michigan, Ann Arbor; Florida Cancer Specialists, Fort Myers; University of Virginia Medical Center, Charlottesville; and Cedars-Sinai Medical Center, Los Angeles, California) and had signed informed consent forms approved by the institutional review board of the treating institution. The institutional review boards of all 8 institutions approved the study. (The full trial protocol is available in Supplement 1.)

Treatment and Assessments

BIND-014 was administered intravenously at a dosage of 60 mg/m² every 21 days along with prednisone at a dosage of 5 mg twice daily until disease progression, until development of a toxic reaction, or until treatment discontinuation at the clinical discretion of the treating physician. Dosage modifications were allowed according to the protocol guidelines for toxic effects. Granulocyte colony-stimulating factor was not administered prophylactically in the first cycle but was allowed in future cycles if a patient experienced an episode of neutropenic fever or at the treating clinician’s discretion on discussion with the medical monitor.

Safety assessments and laboratory studies were performed before administration of each dose. Serum PSA levels and imaging (computed tomography or magnetic resonance imaging and technetium Tc 99m bone scintigraphy) were checked at baseline, every 9 weeks until week 27 and then every 12 weeks thereafter, and at the end of treatment. Imaging studies were analyzed using PCWG2 criteria¹⁷ and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)¹⁸ for measurable disease. The CTC enumeration was performed using the US Food and Drug Administration (FDA)–cleared CellSearch system¹⁹ (Menarini Silicon Biosystems), which uses anti–epithelial cell adhesion molecule antibodies bound to a magnetic ferrofluid and staining for cytokeratins and CD45 to detect cells that meet the definition of a CTC.²⁰ The criteria for a cell to be declared as a CTC included round-to-oval morphology, a visible nucleus (diamidino-phenylindole positive), staining for cytokeratin, and the absence of staining for CD45. This CTC analysis was performed before the administration of BIND-014 at baseline; at weeks 9, 12, 18, and 27 and then every 12 weeks thereafter; and at the end of treatment. The assay detects and enumerates CTCs in peripheral blood, with a limit of detection of 1 CTC per 7.5 mL of blood; therefore, results of cell enumeration are always expressed as the number of cells per 7.5 mL of blood. The CTC counts were reported as unfavorable (≥5 cells per 7.5 mL) or favorable (<5 cells per 7.5 mL), with CTC conversion defined as an unfavorable baseline CTC enumeration decreasing to favorable levels after treatment. For patients with an unfavorable CTC enumeration at baseline, conversion to zero CTC (CTC = 0) was also calculated.²¹

Separately, for the subset of patients treated at Memorial Sloan Kettering Cancer Center, PSMA expression on CTCs was studied using the Epic Sciences non-EpCAM-based CTC detection platform. After red blood cell lysis, all nucleated cells from a blood sample are deposited on glass slides with use of methods described elsewhere for CTC detection.^20,22,23 Two slides are tested per patient sample, corresponding to 6 × 10⁶ nucleated cells or approximately 1 mL of blood. Single-CTC PSMA expression threshold was determined by comparison with PSMA nonexpressing PC3 cells spiked into healthy donor whole blood and processed as patient samples (eFigure 1 in Supplement 2). The Epic Sciences platform can detect single CTCs, clusters of CTCs, and apoptotic CTCs. Only nonapoptotic CTCs were included in the biomarker expression analyses because the effects of the apoptotic cascade on PSMA protein have yet to be characterized.

Statistical Analysis

The primary end point was radiographic progression-free survival (rPFS), with a favorable response defined a priori as rPFS of 6 months or longer. The sample size of 40 patients for this single-stage design was based on an 80% power calculation, such that if more than 26 of 40 patients (65%) had rPFS of 6 months or longer, BIND-014 would be considered to be promising for further investigation. The null hypothesis was that the true response rate is 50%, whereas the alternative hypothesis was that the true response rate is at least 70%. The a priori P value to indicate statistical significance was .04 for the estimation of sample size; P values were 1-sided. Descriptive statistics for the clinical trial cohort were calculated using SAS, version 9.3 (SAS Institute Inc). The statistical analyses generated for the Epic Sciences CTC subset of patients were performed with R packages survival, ggplot2 and survminer (R, version 3.3.0).

Results

Among the 42 patients included in the study, the median age was 66 years (range, 50-85 years), and 34 of 42 patients (81%) were white. Twenty of 42 patients (48%) had received earlier treatment with abiraterone acetate, 5 (12%) had received enzalutamide, 6 (14%) had received both abiraterone and enzalutamide, and 12 (29%) had received radium Ra 223. Sites of metastases included bone in 37 of 42 patients (88%) and visceral spread to the liver and/or lung in 8 of 42 patients (19%). Eighteen of 42 patients (43%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1, and the remainder (14 of 42 patients [57%]) had an ECOG of 0. The median number of treatment cycles was 6 (range, 1-21 cycles). One patient required a dosage reduction. Two deaths occurred during the study but were considered to be unrelated to administration of BIND-014.

Safety

The most common treatment-related adverse events were fatigue (29 of 42 patients [69%]), nausea (23 [55%]), and diarrhea (19 [45%]); 14 patients (33%) reported neuropathy. The majority of toxic reactions were grade 1 or 2. Febrile neutropenia (grades 3 and 4) occurred in 1 of the 42 patients (2%). Treatment-related adverse events are listed in Table 1.

Table 1. Treatment-Related Adverse Events Among 42 Chemotherapy-Naive Patients With Progressing Metastatic Castration-Resistant Prostate Cancer Treated With BIND-014, a Nanoparticle Entrapping Docetaxel, Which Targets PSMA.

Adverse Event	No. (%) of Adverse Events by Cancer Grade
	Any	<3	3 or 4
Hematological
Lymphopenia	11 (26)	6 (14)	5 (12)
Anemia	8.0 (19)	5 (12)	3 (7)
Neutropenia	2 (5)	1 (2)	1 (2)
Leukopenia	2 (5)	1 (2)	1 (2)
Febrile neutropenia	1 (2)	0	1 (2)
Thrombocytopenia	1 (2)	1 (2)	0
Increased tendency to bruise	1 (2)	1 (2)	0
Nonhematological
Fatigue	29 (69)	27 (64)	2 (5)
Nausea	23 (55)	21 (50)	2 (5)
Diarrhea	19 (45)	19 (45)	0
Dyspnea	15 (36)	14 (33)	1 (2)
Decreased appetite	13 (31)	12 (29)	1 (2)
Neuropathy	14 (33)	14 (33)	0
Dysgeusia	11 (26)	11 (26)	0
Stomatitis	10 (24)	10 (24)	0
Alopecia	10 (24)	10 (24)	0

Abbreviation: PSMA, prostate-specific membrane antigen.

Efficacy

Twelve of the 40 patients (30%) with evaluable data experienced a PSA decrease of 50% or greater compared with baseline. Of the 19 patients with measurable disease according to RECIST 1.1 criteria, 6 (32%) had cases that responded to treatment, including 1 patient with complete response and 5 patients with partial responses (2 with unconfirmed and 3 with confirmed responses), and 9 patients had stable disease. The complete response to treatment occurred in a patient with low-volume nodal disease and a small liver metastasis. The patient’s bone metastases were stable according to PCWG2. Overall, the median rPFS was 9.9 months (95% CI, 7.1-12.6 months). The primary end point of this study was rPFS at 6 months, with success defined as rPFS in 26 of 40 patients (65%). The probability of reaching the primary end point (rPFS at 6 months) was 78%. Follow-up data after completion of study therapy were not considered to be sufficient for a projected overall survival.

CTC Conversions Using CellSearch

CellSearch CTC enumeration at baseline was performed on samples from 39 of 42 patients (93%), of whom 26 (67%) had unfavorable counts (≥5 CTCs per 7.5 mL of blood). After treatment, 13 of these 26 patients (50%; 95% CI, 32%-67.9%) showed a conversion to a favorable count (<5 CTCs per 7.5 mL), including 6 (23%; 95% CI, 11%-42%) for whom unfavorable CTC counts at baseline became undetectable (CTC = 0) while participating in the study (Table 2).

Table 2. Decrease in CTCs Among 39 Chemotherapy-Naive Patients With Progressing Metastatic Castration-Resistant Prostate Cancer Treated With BIND-014^a.

Baseline CTC to Best Response CTCb	Patients, No. (%)
>5 to <5	13 (33)
>5 to 0	6 (15)
>5 to >5	13 (33)
<5 to >5	1 (3)
<5 to <5	12 (31)
<5 to 0	7 (18)
0 to 0	5 (13)

Abbreviation: CTCs, circulating tumor cells.

^aBIND-014 is a nanoparticle entrapping docetaxel, which targets prostate-specific membrane antigen.

^bThe CTC enumeration (determined using the CellSearch system; Menarini Silicon Biosystems) is expressed as the number of CTCs per 7.5 mL of blood.

Subset Analysis: Pharmacodynamics of Drug Target on CTCs

To explore the association between PSMA protein expression on individual CTCs and clinical outcomes, additional blood samples were collected from a subset of 18 patients treated at Memorial Sloan Kettering Cancer Center and sent for analysis on the Epic Sciences platform. Samples were obtained from 14 patients at baseline, week 3, and week 9 and from 15 patients at the end of treatment (Figure 1).

Figure 1. Molecular Circulating Tumor Cell (CTC) Characterization Sample Testing CONSORT Diagram.

CONSORT diagram for samples tested for prostate-specific membrane antigen (PSMA) expression on CTCs. There were 18 patients in the PSMA CTC analysis subcohort, and samples were collected at 4 time points, giving 72 potential samples.

At baseline, CTCs were detected in 16 of 18 patients (89%); 11 of these 16 patients (61%) had CTCs that expressed PSMA above the analytical threshold of the assay (PSMA-positive CTCs) (Figure 2A). Visualized per milliliter of blood, the individual subpopulations of PSMA-positive and PSMA-negative CTCs varied considerably from patient to patient (Figure 2B). The median total baseline number of CTCs per patient determined using the Epic Sciences platform was 8.2 nonapoptotic CTCs/mL of blood (range, 0-100 nonapoptotic CTCs/mL of blood); among the 11 patients with PSMA-positive CTCs at baseline, the median number of PSMA-positive CTCs was 3.4 CTCs/mL (range, 0.4-72.4 CTCs/mL). All patients with PSMA-positive CTCs also had other CTCs that were PSMA negative.

Figure 2. Prostate-Specific Membrane Antigen (PSMA) Expression on Circulating Tumor Cells (CTCs) in Individual Patients Before Therapy.

Heterogeneity of PSMA expression on CTCs in individual patients. A, Plot of all patient CTCs detected across 2 slides tested (approximately 1 mL of blood), with the x-axis indicating the PSMA signal to noise ratio detected per CTC. The vertical dotted line indicates the analytical threshold for PSMA signal positivity. B, The intrasample composition by PSMA status, transformed per milliliter.

To assess the changes in CTC populations relative to PSMA expression, we evaluated the samples from the 14 patients who had blood samples obtained at baseline, week 3, and week 9 (Figure 3). The median PSMA-positive CTC populations at weeks 3 and 9 were 1.14 CTCs/mL (range, 0-27.6 CTCs/mL) and 0 CTCs/mL (range, 0-19.8 CTCs/mL), respectively. Two of 14 patients (14%) had week 9 PSMA-positive CTC concentrations greater than their baseline PSMA-positive CTC counts. These 2 patients appeared to have cases that were resistant to BIND-014, with radiographic progression at 1.84 months, whereas the median time to radiographic progression among the 14 patients in this exploratory serial cohort was 5.82 months (95% CI, 3.91-14.92 months).

Figure 3. Changes in Prostate-Specific Membrane Antigen (PSMA) Expression on Circulating Tumor Cells (CTCs) With BIND-014 Treatment.

The PSMA-expressing CTCs are reduced during therapy. A, Plot of all patient CTCs detected across 2 slides tested (approximately 1 mL of blood), with the x-axis indicating the PSMA signal to noise ratio detected per CTC. The vertical dotted line indicates the analytical threshold for PSMA signal positivity. B, Density plot (area under the curve = 1 for both) comparing the distributions of PSMA expression on CTCs from baseline (BL) to week 9 (WK9). The vertical dotted line indicates the analytical threshold of the assay.

Although the small size of the cohort analyzed using the Epic Sciences platform precludes robust overall survival analyses, total CTC burden at baseline was correlated with survival (eFigure 2A in Supplement 2; above vs below cohort median CTC count: 9.5 months [95% CI, 8.13 months–not available] vs 28.2 months [95% CI, 21.57 months–not available]; P < .001), whereas patients without PSMA-positive CTCs at week 9 had a trend for better overall survival compared with patients who had PSMA-positive CTCs (eFigure 2D in Supplement 2; median survival, 20.2 months [95% CI, 8.60 months–not available] vs 7.4 months [95% CI, 6.07–not available]; P = .06), regardless of initial CTC counts.

Discussion

Since the discovery and characterization of PSMA, investigators have exploited the unique diagnostic and therapeutic potential provided by this cell-surface biomarker in prostate cancer management. Optimizing the delivery of chemotherapy to tumors that express PSMA to maximize therapeutic benefit while reducing off-target toxic effects formed the basis for the evaluation of BIND-014, a nanoparticle entrapping docetaxel and its surface functionalized for targeting to PSMA. The results showed that nearly a third of patients with mCRPC experienced PSA decreases of 50% or greater, and 15 of 19 patients (79%; 95% CI, 57%-92%) with measurable disease experienced a partial or complete response or maintained stable disease. The median rPFS time was 9.9 months (95% CI, 7.1-12.6 months), which was beyond the prespecified “favorable” response outcome for the trial (rPFS≥6 months). The agent was also well tolerated, the incidence of neutropenic fever among the study population was low, and the need for dosage reductions because of treatment-related adverse events was rare. Three of 42 patients (7%) experienced grade 3 or 4 anemia while participating in the trial. Despite the potential advantages of this delivery system, neuropathy did occur in a third of patients, which is comparable to the prevalence of neuropathy among patients who receive a standard regimen of docetaxel, and half of the patients in the study reported grade 1 or 2 nausea. These toxic reactions suggest that treatment with BIND-014 is associated with off-target effects on healthy tissue.

Our understanding of both BIND-014 and tumor heterogeneity was enhanced by concurrently measuring total CTC counts using the FDA-cleared CellSearch assay and PSMA expression on CTCs before and after treatment with use of the Epic Sciences platform. At the time of trial entry, 26 of 39 patients (67%; 95% CI, 51%-79%) had unfavorable CTC counts (≥5 cells per 7.5 mL of blood), reflective of a poor prognosis. Half of these patients (13 of 26 patients [50%; 95% CI, 32%-67.9%]) experienced a decrease in CTC count to less than 5 cells per 7.5 mL of blood, and 6 of these 26 patients (23%; 95% CI, 11%-42%) had decreases in CTC count to 0 cells per 7.5 mL of blood after treatment. Put in perspective for historical comparison, the phase 3 COU-AA-301 trial, in which the survival benefit associated with receipt of abiraterone and prednisone among a population of patients who had received chemotherapy was established, found that 53% of the 1195 patients had 5 or more CTCs per 7.5 mL of blood, of whom only 14% showed a conversion to less than 5 CTCs per 7.5 mL of blood after therapy.²⁴ In the COU-AA-301 analysis, overall survival was markedly improved among patients who experienced CTC conversion (median overall survival, 17.0 months vs 7.5 months). A separate meta-analysis across 5 phase 3 randomized clinical trials validated CTC conversion and CTC = 0 as measured by CellSearch for high discriminatory power of predicting overall survival.^21,25

Further insights into the selection of patients who might benefit from BIND-014 therapy came from our subset analysis of PSMA expression before and after treatment among the 18 patients from whom CTCs were isolated using the Epic Sciences platform, which enabled monitoring of disease status from multiple lesions on a repeated basis in a manner that is not feasible with serial single-site tissue biopsies. Paired biopsy and single-cell molecular profiling in other studies suggests that there are similarities between tissue and CTCs.^{26,27,28,29,30} In this trial, 2 principal lessons are worth highlighting: the reduction in both total CTCs, which is a marker of clinical benefit, and specifically PSMA-positive CTCs suggests that the detection of PSMA-positive CTCs before treatment can be used to identify patients who are most likely to benefit in addition to serving as a pharmacodynamic measure. Second, there was marked intrapatient and interpatient heterogeneity of PSMA expression on CTCs. This underscores the complexity of targeting tumors with single cell-surface markers.

The number of PSMA-positive CTCs selectively decreased after treatment with this nanoparticle with PSMA-targeting peptides, BIND-014. Conclusions are limited by the sample size analyzed; however, if validated in future studies, the results have implications for monitoring patients serially and the opportunity to provide further benefit through early administration of additional therapies directed at the non–PSMA-expressing cell populations, with the choice of therapy made on the basis of the biological interrogation of the surviving cell population. The findings further highlight the importance of serial biological profiling of an individual patient’s disease as it evolves over time and the need for the development of diagnostic tests that provide the information needed to inform a treatment decision in “real time.”

A second key finding from the correlative studies was the heterogeneity of PSMA expression levels in CTCs. Although most patients with available CTCs did have some PSMA-positive CTCs, cells that did not express the protein were also present, and the ratio between PSMA-positive CTCs and PSMA-negative CTCs varied by patient. Pathology studies of primary and metastatic prostate tumors have also demonstrated that PSMA expression assessed by immunohistochemistry can be heterogeneous. In a series that reported matched samples from 51 patients with metastatic prostate cancer, 49 of 51 primary tumors (96%) and 43 of 51 metastatic tumor biopsies (84%) were considered to be PSMA positive, whereas 2 primary tumors (4%) and 8 metastatic samples (16%) were considered to be in the negative range as defined by the study; however, 7 of 51 primary samples (14%) and 6 of 51 metastatic samples (12%) showed highly heterogeneous PSMA expression.³¹

The heterogeneity of PSMA expression on CTCs both within and between patients seen in this trial also challenges the thinking that PSMA expression is ubiquitously expressed in metastatic prostate cancer, and this has implications for PSMA-directed therapies. The results suggest that combining PSMA-directed approaches with sequential or concurrent administration of therapies that are directed at the non–PSMA-expressing cell population may be beneficial. In addition, establishing the threshold frequency and level of PSMA expression on individual cells (reported as a percentage of the total number present and the absolute expression) that gauges clinical benefit as well as understanding the mechanisms of resistance in cells with PSMA levels above the threshold are critical unmet needs. Use of CTCs to measure PSMA expression in practice could also be enhanced with the now more widely available PSMA-directed positron emission tomography imaging tracers, which provide information on both the level of expression and heterogeneity between metastatic tumor sites in individual patients. To date, the correlation between PSMA positron emission tomography (eg, changes in standard uptake value in lesions) and clinical response to PSMA positron emission tomography–directed agents is largely anecdotal, but promising trials are under way to answer such questions.

Limitations

As a single-arm trial, this study is unable to assess the efficacy of BIND-014 relative to docetaxel. In addition, although CTC analyses focused on PSMA expression provide interesting correlative data, interpretation is limited by the sample size.

Conclusions

Many aspects of our study—reductions in PSA, radiographically confirmed disease control in bone and visceral metastatic disease, favorable CTC conversions, and an acceptable adverse effect profile—were promising for BIND-014. However, standard therapy with docetaxel is widely used and effective in treating this disease, and as a natural comparator for a phase 3 randomized clinical trial with BIND-014, it sets a high bar for efficacy in an unselected population. Decreases in PSMA-positive CTCs, however, occurred early and robustly in this trial, which provides a rationale for the hypothesis that PSMA expression could function as a patient selection biomarker and potentially an early response measure in future trials. Selecting patients with pretreatment PSMA-positive CTCs remains a promising strategy for PSMA-targeted therapy that could hold a therapeutic and toxicity advantage over docetaxel-based chemotherapy.

Supplement 1.

Trial Protocol.

Supplement 2.

eFigure 1. Images of Prostate-Specific Membrane Antigen (PSMA)-Positive Circulating Tumor Cells (CTCs)

eFigure 2. Overall Survival by Baseline and Week 9 Circulating Tumor Cell (CTC) Count and Prostate-Specific Membrane Antigen (PSMA)-Positive CTC Count