For men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), a docetaxel-containing nanoparticle directed against prostate-specific membrane antigen (PSMA) was both active and well tolerated.

Among 42 men with mCRPC that had progressed after treatment with abiraterone acetate (Zytiga) and/or enzalutamide (Xtandi), the 6-month radiographic progression-free survival (PFS) rate, the primary endpoint, was 65%, and approximately one-third of evaluable patients had a prostate-specific antigen (PSA) response and measurable disease response, reported Karen A. Autio, MD, MSc, of Memorial Sloan Kettering Cancer Center, New York, and her colleagues.

Treatment with the PSMA-directed docetaxel-containing nanoparticle, called BIND-014, was also associated in some patients with a rapid and robust decline in PSMA-positive circulating tumor cells (CTCs), the investigators noted. The report was published in JAMA Oncology.

“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,” they wrote.

Their findings suggest that patients with PSMA-positive CTCs might be good candidates for treatment with BIND-014, which is associated with lower toxicities than standard docetaxel, the investigators said.

In the open-label phase 2 trial, 42 men (median age 66) with chemotherapy-naive mCRPC that had progressed on abiraterone and/or enzalutamide were treated with intravenous BIND-014 at dosages of 60 mg/m² on the first day of each 21-day cycle, plus prednisone 5 mg twice daily, until disease progression, intolerable toxicity, or treatment discontinuation at the treating physician’s discretion.

The median number of doses delivered was six.

Of 40 evaluable patients, 12 (30%) had a PSA response, defined as a decrease of 50% or greater from baseline. Among 19 patients with disease measurable according to Response Evaluation Criteria in Solid Tumors, version 1.1, six (32%) had responses, including one complete response and five partial responses. Nine other patients had stable disease.

The median PFS was 9.9 months. As noted, the radiographic PFS rate at 6 months was 65% (26 of 40 patients).

CTC enumeration was performed on samples from 39 patients, of whom 67% had unfavorable counts at baseline, defined as 5 or more CTCs per 7.5 mL of blood.

After treatment, 13 of the patients had a conversion to a favorable count, including 6 whose CTCs became undetectable.

The most common treatment-related adverse events were fatigue, occurring in 69% of patients, nausea in 55%, diarrhea in 45%, and patient-reported neuropathy in 33%. Most toxicities were grade 1 or 2.

Grade 3 or 4 hematological toxicities included lymphopenia in five patients, anemia in three, neutropenia in one, leukopenia in one, and febrile neutropenia in one.

Nonhematological grade 3 or 4 events included fatigue and nausea in two patients each, and dyspnea and decreased appetite in one patient each.

“In this trial, two 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,” the investigators wrote.

“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,” they wrote.

SOURCE: Autio KA et al. JAMA Oncol. 2018 July 5 doi: 10.1001/jamaoncol.2018.2168.

PSMA-targeting docetaxel nanoparticles active, safe for mCRPC