U.S. Food and Drug Administration ( FDA ) staff report did not find clear evidence of effectiveness for Abbott Laboratories’ experimental prostate cancer drug, Xinlay.

The FDA reviewed design, efficacy and safety of two randomized studies of Atrasentan ( Xinlay ) for men with metastatic, hormone-refractory prostate cancer.

One of these studies is a phase III study ( M00-211 ) and the other is a phase II study ( M96-54 ).

Although time to disease progression is the primary endpoint for both studies, the two studies differ in the treatment population, design and definition of disease progression.
The formulations used in the two studies are not bioequivalent by FDA standards.
Furthermore, the design of the phase II study is not acceptable for a registration study.

According to FDA staff report the results of these studies cannot be pooled together.


Phase III study ( M00-211 )

The phase III study, M00-211 is a well-designed, prospectively randomized, double blind study in patients with hormone-refractory prostate cancer with rising PSAs.
The primary endpoint is time to disease progression defined as time from randomization to first event of disease progression.
Eight hundred and nine patients without a history prior treatment for prostate cancer were randomized to one of two arms; placebo ( n=401 ) and 10 mg of Atrasentan ( n=408 ). The patients ingested the study drug daily until tumor progression, or toxicity.
The study failed its primary endpoint of intent-to-treat analysis of time to disease progression.
It also failed 4 of 5 secondary endpoints which were overall survival, change in bone scan index, time to PSA progression and progression-free survival. The 5th endpoint, mean change in alkaline phosphatase ( ALP ) reached statistical significance. However, a mean change of 20 ng/mL has questionable clinical relevance.
The study also failed many of its tertiary endpoints. These failed tertiary endpoints were Quality of Life adjusted time to disease progression ( QATTP ), Karnofsky performance status and mean change from baseline in PSA.


Phase II trial ( M96-594 )

The phase II trial was a randomized study in men with hormone refractory prostate cancer. Two hundred and eighty eight men with rising PSA were enrolled to one of three arms: placebo ( n= 104 ), 2.5 mg of Atrasentan ( N=95 ) and 10 mg of Atrasentan ( N=89 ).
Almost all patients in the phase II study had a history of prior therapies as opposed to the phase III study which specified that no prior therapy other than hormonal therapy should have been administered previously. Patients on the placebo arm were more heavily pretreated than on the Atrasentan arms.
Protocol violations in this phase II study were even greater than in the phase III study. An excessive number of protocol violations were observed.
As with the phase III study, this phase II study failed its primary objective of time to disease progression. This phase II study does not provide substantial evidence of efficacy and is not supportive of approval because of its weak study design, conduct and results.


Safety

Four hundred and four patients who received Atrasentan 10 mg were evaluable for safety on the phase III study. The 48 patients on the 10 mg Atrasentan arm of the phase II study are not combined with the patients on the phase III study because of questionable bioequivalence of the formulations used.
In the order of decreasing frequency, the common adverse events ( ADs ) ( any grade and greater than 10% in frequency ) observed on the phase III study are bone pain, peripheral edema, rhinitis, pain, headache, constipation, asthenia, infection, nausea, anemia, anorexia, back pain and dyspnea.
The incidence of pain, bone pain, constipation, nausea, anorexia and asthenia were similar on the Atrasentan and placebo arms.
In the phase II study the common AEs >10% in frequency are anemia, constipation, anorexia, asthenia, abdominal pain, headache and rhinitis.
Numerically, there were more deaths on the Atrasentan arm ( N=166, 41% ), compared to the placebo arm ( N=158, 39% ) on the phase III study. This arm also had more deaths from cardiovascular causes ( Atrasentan N=8; placebo N=2 ).
Atrasentan is known to cause congestive heart failure ( CHF ) from previously performed Phase II trials.
In phase III study an increase in number of arrhythmias and cardiovascular events ( myocardial infarction, angina pectoris and stent placements ) was observed on the Atrasentan arm in addition to an increase in CHF ( Atrasentan 40%, placebo 13% ). Twenty patients on the Atrasentan arm experienced 24 arrhythmia events, and 5 patients on the placebo arm were reported to have 5 events of arrhythmias. Six patients on the Atrasentan arm had grade 3 or 4 CAD toxicity ( myocardial infarction, angina pectoris or stent placement ) as opposed to 2 patients on the placebo arm with grade 3 or 4 toxicity. This finding was also seen in the Phase II study.
Ten patients on the Atrasentan 10 mg arm and 2 patients on the placebo arm had at least one incidence recorded of coronary artery disease ( CAD ).
Eleven patients on the Atrasentan 10 mg arm and 8 on the placebo arm had arrhythmias.

Source: FDA, 2005


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