Early Trials Point to Novel Treatments for Select mCRPC Patients

Preliminary metastatic prostate cancer results reported for aurora kinase A inhibitor in neuroendocrine disease and programmed cell death protein 1 inhibitor therapy for castration-resistant patients

medwireNews: Early results from two phase II trials indicate that the aurora kinase A (AURKA) inhibitor alisertib and the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab may have potential for select groups of patients with metastatic castration-resistant prostate cancer (mCRPC).

Findings from both studies were presented at the ESMO 2016 congress, held in Copenhagen, Denmark.

Himisha Beltran, from Weill Cornell Medical College in New York, USA, reported data for alisertib 50 mg twice daily over 7 days in a 21-day cycle in 60 patients with neuroendocrine prostate cancer, defined as tumours with small cell or neuroendocrine histology (67%), clinical suspicion of neuroendocrine status based on at least one neuroendocrine morphological (23%) or immunohistochemical marker (18%), or new liver metastases without prostate-specific antigen (PSA) progression (27%).

She explained that patients rarely underwent metastatic biopsy at the time of the trial for clinical purposes but that all participants in the current study underwent metastatic biopsy before treatment; central review confirmed a neuroendocrine diagnosis in 48% of the patients.

More than half (54%) of the patients had Gleason grade 8–10 and patients commonly had metastases to bones (78%), lymph nodes (75%), liver (60%), any visceral metastases (67%) and/or lungs (37%). The majority (78%) had received local therapy and the median number of prior treatments was three, including enzalutamide or abiraterone, and docetaxel or platinum-containing chemotherapy.

Median progression-free survival (PFS) was 8.7 weeks; the primary endpoint of 6-month PFS was achieved by 12.6% of patients, which was below the pre-specified 30% threshold required to consider the agent worthy of further exploration. But the percentage of patients reaching this endpoint differed between those with adenocarcinoma histology and those with neuroendocrine histology, at 7.1% versus 15.2%.

Median overall survival was 9.5 months and did not differ by histology. Grade 3 or 4 toxicity was consistent with earlier trial reports for alisertib and occurred in 38% of patients, most commonly neutropenia (13%).

Beltran explained that while the number of patients in the study was small, those who had at least a partial response to alisertib scored higher for neuroendocrine features and lower for androgen receptor signalling than those who did not.

And she reported further analysis from three individuals with an “exceptional” response or long-term disease stability, all of whom had neuroendocrine disease. This included a patient with symptomatic mCRPC including bone metastases and bulky retroperitoneal and pelvic disease who had continued with alisertib for 3.5 years. He was diffusely positive for neuroendocrine markers and showed both N-MYC and AURKA gene amplifications and a hypermutation rate.

A second man with small-cell neuroendocrine disease achieved clinical improvement within three cycles of alisertib, including near-complete resolution of liver metastases, complete resolution of lung metastases and he remained in complete remission for 14 months. But he had the drug withheld to undergo surgery and during this time experienced rapid progression including brain metastases and died without being able to restart alisertib.

Himisha Beltran said that this patient’s pretreatment and progression biopsy and circulating tumour DNA results were “notable” for being “completely identical” genome-wide, “suggesting that lack of heterogeneity may be a mediator of response in this case.”

She added that organoids successfully grown from biopsy samples taken from patients who did and did not respond to alisertib showed a laboratory response to the agent that mirrored the clinical response and may offer a good model system to help understand response and resistance to treatment.

Indeed, the team identified an assay to measure levels of an Aurora–N-MYC complex that is disrupted by treatment with alisertib; the organoid derived from the nonresponder showed extremely high levels of the complex despite alisertib exposure, indicating that this may act as a biomarker for response to the agent, the presenter said. It also “suggests that some of the newer drugs that better target this complex may be a more effective therapeutic approach in this case”, she added.

Preliminary phase II results were also reported for mCRPC patients who had progressed on enzalutamide but continued with the anti-androgen therapy while receiving pembrolizumab 200 mg every 3 weeks for an initial four doses, with further treatment in the absence of progression.

The PD-1 inhibitor trial was initiated after research suggested that enzalutamide therapy is associated with an increase in programmed death ligand 1 (PD-L1) expression, explained presenting author Julie Graff, from the Knight Cancer Institute in Portland, Oregon, USA.

Of the first 28 patients treated with pembrolizumab, 25 have completed therapy, three patients are midtreatment and two have begun a second course.

In all, 19% of the first 27 patients in the trial achieved the primary endpoint of a confirmed PSA reduction of 50% or greater, and in a subgroup of 19 patients with longer follow-up, 21% achieved stable disease for at least 6 months without a PSA response. Median PFS is 34 weeks.

Graff demonstrated a steep decrease in PSA in five responders, including one patient whose level fell from 2502.75 to below 0.01 ng/mL. She emphasized that none of the responders have relapsed, prompting her to say that combined enzalutamide plus pembrolizumab may achieve “profound clinical responses both biochemically and radiographically”.

But she cautioned: “Further study is needed before pembrolizumab is used in the routine clinical care of mCRPC.”

Grade 3 or more severe immune-related adverse events included urinary tract infection and myelitis in one patient, both of which were resolved, and colitis in two patients that required high-dose steroids, plus infliximab in one case. Two patients required thyroid replacement therapy.

Noting that the majority of patients had Gleason grade 8–10 disease, invited discussant Winald Gerritsen, from Radboud Medical Centre Nijmegen in the Netherlands, said that the PSA responses were “remarkable” for having achieved at least a 90% reduction quickly. It is worth mentioning, he added, that very good radiological responses have already been seen, including two patients who have not experienced progressive disease for over a year. 

References

ESMO 2016 Congress; Copenhagen, Denmark: 7–11 October

LBA29 - A phase 2 study of the aurora kinase A inhibitor alisertib for patients with neuroendocrine prostate cancer (NEPC)

719O - First evidence of significant clinical activity of PD-1 inhibitors in metastatic, castration resistant prostate cancer (mCRPC)

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