Apatorsen Fails To Boost Inoperable Urothelial Carcinoma Survival

Antisense oligonucleoside therapy against heatshock protein 27 does not increase survival above that achieved by first-line chemotherapy for advanced urothelial carcinoma

medwireNews: Adding apatorsen to first-line chemotherapy does not improve overall survival (OS) in patients with inoperable advanced urothelial carcinoma, investigators say.

However, the researchers believe that the antisense oligonucleotide, which targets heatshock protein (Hsp)27, may have shown some efficacy in patients with poor prognostic features, in particular those with high levels of Hsp27.

“Additional studies will be required to support the evidence that [serum] Hsp27 is a potential prognostic and/or predictive biomarker of response to apatorsen treatment”, they write in the Annals of Oncology.

For the phase II trial, 183 patients were given apatorsen at a dose of 600 mg (n=60) or 1000 mg (n=61) every 2 days, or placebo (n=62), followed by up to six cycles of gemcitabine–cisplatin chemotherapy. Patients without disease progression were allowed to continue with apatorsen until disease progression or unacceptable toxicity.

Patients using the 600 mg or 1000 mg doses of apatorsen did not have significantly longer OS than those given placebo, at a median of 15.3 and 15.6 months versus 15.0 months, respectively, report Joaquim Bellmunt, from Hospital del Mar in Barcelona, Spain, and co-authors.

Median progression-free survival (PFS) was also comparable, at 7.5 months for both apatorsen arms versus 6.2 months with placebo.

The overall response rate was 57% and 50% with the 600 mg and 1000 mg apatorsen doses versus 61% with placebo, with median response durations of 8.5, 7.2 and 5.1 months, respectively. An objective response was achieve by a corresponding 48%, 42% and 54% of patients, with disease control rates of 76%, 72% and 79%, respectively.

In all, 22 patients given the 600 mg dose, 26 patients given the 1000 mg dose and 32 patients given placebo had a poor prognosis, defined as a Karnofsky Performance Status of 80% or below, liver involvement, low haemoglobin or high alkaline phosphatase.

For patients with poor prognosis, the apatorsen 600 mg dose achieved slightly better results than placebo for both OS (11.9 vs 9.0 months, hazard ratio [HR=0.72) and PFS (5.6 vs 4.6 months, HR=0.78).

But placebo offered better PFS than the 1000 mg dose, which the researchers attribute to a lower median number of cycles and a higher rate of treatment discontinuation due to adverse events with the high dose.

Side effects more commonly associated with apatorsen treatment at either dose than with placebo included pyrexia, peripheral oedema, abdominal pain, peripheral neuropathy and chills, with back pain and haematuria the most common adverse events with the 1000 mg dose.

The researchers believe that baseline serum Hsp27 levels may have “prognostic value”, finding that patients with a concentration above the median of 5.5 ng/mL had significantly poorer survival than those with lower levels (HR=2.01).

They say that baseline Hsp27 serum levels were higher in the poor prognosis than good prognosis patients, and that further analysis suggested a trend towards better survival with apatorsen for poor prognosis patients who achieved a reduction in serum Hsp27 area under the curve at day 100 than their placebo-treated counterparts.

“Since the poor-prognosis patients who achieved lower Hsp27 [area under the curve] levels during the first 100 days of treatment appeared to benefit more in both the 600 mg and 1000 mg arms, [serum] Hsp27 levels should be explored in future trials as a potential biomarker to predict response to apatorsen treatment”, the investigators recommend.

But they add that as clinical trials comparing immune checkpoint inhibitors in fit or unfit patients are ongoing, “the role of apatorsen – if any – will be restricted to a highly accurate biomarker selected population that is not suitable for [immuno-oncology therapies].”

Bellmunt J, Eigl BJ, Senkus E, et al. BOREALIS-1: A randomized, first line, placebo-controlled phase 2 study evaluating apatorsen and chemotherapy for patients with advanced urothelial cancer. Ann Oncol; Advance online publication 24 July 2017. DOI: https://doi.org/10.1093/annonc/mdx400

medwireNews is an independent medical news service provided by Springer Healthcare. © 2017 Springer Healthcare part of the Springer Nature group.