Trial investigator Neal Shore told BioWorld that Bayer AG's just-approved oral androgen receptor inhibitor (ARI), Nubeqa (darolutamide), for non-metastatic castration-resistant prostate cancer (CRPC) brings a pronounced advantage in adverse events (AEs) over two other approved oral drugs in the class.

"When I look at the safety and adverse event [AE] profile [from the phase III trial called Aramis] in conjunction with my own experience, having been involved in the earlier-phase studies, I can with a great deal of confidence say to a patient in their mid-70s or 80s that this drug has so far reported a cleaner and best-in-class" record in terms of the known AEs in men taking ARIs, said Shore. He is the medical director of the Carolina Urologic Research Center, practices with Atlantic Urology Clinics in Myrtle Beach, S.C., and was the principal Aramis investigator at his site. "I think it would be misleading to say one drug is going to give you a better quality of life than another until you do comparator studies, and those are ongoing," he said, adding that he is involved with those efforts as well.

Aramis tested Nubeqa plus androgen deprivation therapy (ADT) and showed a highly significant improvement in the primary efficacy endpoint of metastasis-free survival (MFS), with a median of 40.4 months vs. 18.4 months for placebo plus ADT (p<0.0001). MFS is defined as the time from randomization to the time of first evidence of blinded, independent, central review-confirmed distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. In patients with the stage of CRPC for which Nubeqa is indicated, physicians mainly aim to delay the spread of disease. The drug was approved three months ahead of the targeted action date under priority review.

In the U.S., more than 73,000 men are expected to be diagnosed with CRPC this year. About 40% will have disease that has not yet metastasized and is associated with a rising prostate-specific antigen (PSA) level, despite a castrate-level measure of testosterone. Within two years, disease will spread in about one-third of those patients. PSA monitoring helps identify them early.

Nubeqa goes up against other nonsteroidal androgen receptor inhibitors already on the market, New York-based Pfizer Inc.'s Xtandi (enzalutamide) and New Brunswick, N.J.-based Johnson & Johnson's Erleada (apalutamide). Xtandi was first approved in the summer of 2012, with an indication of non-metastatic CRPC added last July, and Erleada gained the FDA's go-ahead in February of last year.

In Aramis, both arms showed a 9% percent discontinuation rate due to adverse reactions, and the most frequent ones requiring dropout of Nubeqa patients were cardiac failure (0.4%) and death (0.4%). Adverse reactions turning up more frequently in the Nubeqa arm (≥2% over placebo) were fatigue (16% vs. 11%), pain in extremity (6% vs. 3%) and rash (3% vs. 1%). Nubeqa was not studied in women and there is a warning and precaution for embryo-fetal toxicity, Bayer noted.

Aramis enrolled patients who were receiving a concomitant gonadotropin-releasing hormone analogue or had a bilateral orchiectomy. The study randomized 1,509 patients in a 2-to-1 ratio to receive 600 mg of Nubeqa orally twice daily or placebo plus ADT. Patients with a history of seizure were allowed in the study. "The other two [approved drugs'] trials absolutely forbade, and it was exclusionary, [having] patients who had any seizure risk or were on any seizure-lowering medication," Shore said, noting that Nubeqa "from a biomolecular standpoint is a markedly different-looking drug" vs. the other two, which probably explains the lower blood-brain barrier penetration.

'Three really good drugs'

Wainwright analyst Raghuram Selvaraju spoke with another prostate cancer expert, Emmanuel Antonarakis, associate professor at Johns Hopkins School of Medicine and medical oncologist at the Sidney Kimmel Comprehensive Cancer Center in Baltimore, who agreed with Shore. He said that, while Xtandi and Erleada are "virtually interchangeable – and, indeed, differ by only a single substituent from a chemical structure standpoint – darolutamide is different and may be deemed superior, particularly from a safety perspective." While the other two drugs are linked to fatigue and loss of balance, the Bayer compound could "eventually ascend to the leadership position" among second-generation ARIs, in Antonarakis' opinion.

Overall survival (OS) and time to pain progression were additional secondary efficacy endpoints in Aramis, but OS data were not yet mature at the time of final MFS analysis. The MFS result was supported by a delay in time to pain progression – defined as at least a two-point worsening from baseline of the pain score on Brief Pain Inventory-Short Form or the start of opioids – in patients treated with Nubeqa as compared to placebo, Bayer said. Pain progression was reported in 28% of all patients in the study.

Bayer, of Leverkusen, Germany, has filed for approval of Nubeqa in the EU, Japan and elsewhere. The drug is being developed jointly by Bayer and Orion Oyj, of Espoo, Finland. Bayer's Xofigo (radium Ra 223 dichloride) was approved in May 2013. Xofigo is used to treat prostate cancer that no longer responds to hormonal or surgical treatment that lowers testosterone. It's indicated for men whose disease has spread to the bone with symptoms but not to other parts of the body.

"In terms of OS, we see trends that are not yet to the point [where] one can say they are statistically significant" with ARIs, Shore said. But OS findings with each of the approved compounds are due "sometime next year. I look forward to seeing those. I'm cautiously optimistic that they'll be positive in all three trials." Until head-to-head trials are conducted, it's unfair to attempt ranking efficacy, he said. Jefferies analyst James Vane-Tempest, who covers Orion, tried anyway. Darolutamide is one "key driver of mid-term growth, but it could be tough to penetrate the hormone prostate cancer therapy, given the already established products such as Xtandi and Erleada," he wrote in a June 5 report. "Recent phase III data showed the product is well-tolerated and shows limited to no difference to the safety profile of placebo; however the efficacy wasn't as good as that shown with Xtandi and Erleada," in his view.

"All three drugs work – all three are really good drugs," Shore said. They have yielded comparable MFS improvements with similar hazard ratios, exceptional delays in PSA rises as well as time to next anti-neoplastic therapy, with "very similar Kaplan-Meier curves and beautiful declines in the waterfall plots." Settling on which drug to use should happen through a "patient-physician shared decision-making review" that takes into account co-morbidities and other factors, he said. "A lot of people will say, 'Well, this is an asymptomatic population.' It is, but not entirely. These are men who have been on androgen-suppressive medication for at a minimum months and often times for years. There are sequellae associated with that."

Nubeqa will be available within the next week, Bayer said, with a wholesale acquisition cost of $11,550 for a 30-day supply of 300-mg tablets.