Results from the Phase III ALSYMPCA trial suggest Alpharadin, which is slated for FDA filing in mid-2012, could get labeling suggesting suitability for treatment of castration-resistant prostate cancer patients pre- or post-chemotherapy and noting a benefit for prevention of skeletal related events, according to Algeta execs.

Alpharadin (radium 223-chloride) is a radiopharmaceutical partnered with Bayer (Also see "Algeta Recruits Bayer To Deliver Prostate Cancer Drug Alpharadin To Market" - Pink Sheet, 3 September, 2009.). A September 2009 deal on the drug gave Algeta a 50/50 co-promote option in the U.S. as well as profit-sharing.

On Sept. 24 at the European Multidisciplinary Cancer Congress in Stockholm, researchers presented the Phase III ALSYMPCA study in 922 patients with CRPC with symptomatic bone metastases. Previously, the company reported that the drug had met the primary endpoint of overall survival in ALSYMPCA and that the study would be halted to allow patients to cross over to the treatment arm (Also see "Positive Data On Bayer/Algeta's Alpharadin Could Accelerate Filing Timeline" - Pink Sheet, 6 June, 2011.).

The treatment is one of several new candidates to show a survival benefit in tough-to-treat CRPC, including Dendreon's Provenge (sipuleucel-T), Johnson & Johnson's Zytiga (abiraterone) and Sanofi's Jevtana (cabazitaxel) (Also see "Prostate Cancer Market Snapshot: More Than Provenge" - Pink Sheet, 22 November, 2010.).

Algeta is focusing on patients who have bone metastases. About 75% of these patients are not eligible for docetaxel chemotherapy or have failed docetaxel treatment.

In ALSYMPCA, participants were randomized 2:1 to Alpharadin plus best standard of care, or placebo and best standard of care, which included steroids, painkillers, bisphosphonates and the hormonal therapies ketoconazole and estrogen. Those in the treatment arm received up to six injections of the radiopharmaceutical.

Among other findings, the company reported that median overall survival in the treatment arm was was14 months compared to 11.2 months, which translates into a 2.8 month benefit for survival. The drug also performed well on secondary endpoints, for example, the median time to first skeletal related event was 13.6 months compared to 8.4 months, a 64% improvement. And researchers noted a 49% improvement in prostate-specific antigen progression in the treatment arm, but response rates are not yet available.

Safety findings in ALSYMPCA were encouraging, with the most common effect being nausea (34% for Alpharadin vs. 32% for placebo) and diarrhea (22% and 13%, respectively) and constipation (18% and 18%). The incidence of Grade 3 or Grade 4 neutropenia was 2% for Alpharadin and 1% for placebo. Bone pain was less common in the treatment arm (43% for Alpharadin compared to 58% for placebo). Overall, the incidence of adverse events and serious adverse events was lower in the Alpharadin arm.

The lower rate of side effects in the treatment arm is "highly unusual" for cancer drugs, said Chief Medical Officer Gillies O'Bryan-Tear, commenting on results in a Sept. 26 investor briefing.

The favorable safety profile means that Alpharadin could one day find a role in combination therapy, possibly with abiraterone, once bone metastases are evident on scans, according to the company.

Asked about prospects for labeling during the call, Algeta execs said that they could not second-guess FDA. However, CEO Andrew Kay also noted that the protocol had been pre-agreed with the agency and that labeling usually reflects trial results. Furthermore, the findings were robust across patient groups, that is, whether participants had failed chemotherapy or were not able to have it for some reason.

As to whether a claim for SRE prevention could make it into the label, execs said that they did expect that the findings would be included in the ultimate labeling, though perhaps not in the indication section. "But that's a matter for regulatory authorities," O'Bryan-Tear said.

Analysts attending the briefing questioned the drug's competitive profile relative to Amgen's Xgeva (denosumab), which is indicated for SRE prevention in cancer patients and under review for prevention of bone metastases in prostate cancer (Also see "New Oncology Indications Should Continue Denosumab’s Upward Trajectory" - Pink Sheet, 26 September, 2011.).

Algeta execs responded by highlighting the different mechanisms and Alpharadin's survival benefit. "This is a completely different kind of drug with a completely different kind of mechanism of action," said O'Bryan-Tear. "You can't compare Alpharadin, which prolongs life, with a bone-strengthening drug like denosumab. None of the bone-strengthening drugs, including denosumab, have ever shown that they can prolong survival in this condition."

Surveying Prostate Cancer Market

During the call, execs said that they plan to focus their efforts on reaching urologists, who typically manage patients who are not eligible for chemo, as well as oncologists.

That could make for better uptake, as there can be problems with uptake of radiation drugs with medical oncologists. Writing in a Sept. 26 note about the European cancer meeting, Cross Current Research analyst Alex To noted that "in other cancers, systemic radiopharmaceuticals have not done well historically."

With experience in implantation of radiation seeds, urologists are more comfortable with radiopharmaceuticals than oncologists, but in the post-chemo late-stage cancer settings, patients are typically managed by oncologists, To noted.

Alpharadin's survival benefit is more modest than what was reported for Zytiga (4.6 months) post-chemotherapy, and Provenge (4.1 months) in asymptomatic patients prior to chemotherapy, but the patient populations were less advanced for both of these drugs. Jevtana had shown a 2.4 month survival benefit in patients who had failed docetaxel-containing chemotherapy regimens, though its labeling includes extensive safety warnings, including a boxed warning about the potential for neutropenic death ([A#0720250001]).

Given that so many drugs have now shown a survival benefit, To suggested that new treatments will need to show more than a survival benefit to compete, a demonstration of improved pain symptoms, for example.

Provenge's disappointing launch has been attributed to miscalculations about reaching urologists, reimbursement issues and lack of effect on conventional markers urologists are accustomed to monitoring, such as PSA and tumor size (Also see "With Dendreon Humbled, Lessons Learned For Cancer Vaccine Makers" - Pink Sheet, 22 August, 2011.).

- Emily Hayes (e.hayes@elsevier.com)

Phase III Results For Bayer/Algeta's Alpharadin Hint Of Labeling Down The Line

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