Astellas (TYO:4503)/Medivation’s
(NASDAQ:M_DVN) Phase II TERRAIN study topline data on Xtandi has left experts
questioning whether it will be moved into earlier lines of treatment for
metastatic castration-resistant prostate cancer (mCRPC) patients naive to
chemotherapy.
While one oncologist said the TERRAIN data
justifies moving Xtandi up, others said they would continue using it in later
lines of treatment of pre-chemotherapy mCRPC. Meanwhile, the availability of
the TERRAIn study’s (NCT01288911) comparator drug, the generic bicalutamide,
which belongs to the same class as Xtandi, may discourage payers and pharmacy
benefit managers (PBMS) from covering Xtandi in earlier lines, two health
system pharmacists said.
According to an analyst report, however, the
TERRAIN data is expected to drive use of Xtandi over bicalutamide and
eventually lead to the latter’s replacement. The report noted that bicalutamide
is currently the most-prescribed drug in prostate cancer. Bicalutamide is the
generic name of AstraZeneca’s (LON:AZN) Casodex, though several companies now
make generic versions.
TERRAIN is a randomized, double-blind,
parallel-assignment trial of Xtandi in 375 patients whose disease has
progressed while on a luteinizing hormone receptor hormone (LHRH)
agonist/antagonist or after receiving a bilateral orchiectomy, according to
Clinical Trials.gov.
The Astellas spokesperson declined to comment
on how the TERRAIN results might affect uptake of Xtandi, but noted that the
full TERRAIN data, including additional safety data, will be presented at the
European Association of Urology’s 2015 meeting, which takes place 20-24 March
in Madrid, Spain.
Earlier treatment questionable
If patients’ prostate specific antigen (PSA)
rises after local therapy or if they have metastatic disease, then doctors can
start with bicalutamide/AbbVie’s (NYSE:ABBV) LHRH agonist Lupron (leuprolide),
and then stop bicalutamide in the first month, said Dr. Tian Zhang, medical
oncology fellow, Duke University, Durham, North Carolina. Sometimes, she said.
Patients will respond to that regimen, but if their PSA levels rise later,
doctors will re-challenge with bicalutamide and see if the tumor responds.
After exhausting those therapies, doctors will use Xtandi or Janssen’s Zytiga
(abiraterone), she said.
The TERRAIN trial showed a progression free
survival (PFS) benefit, and not an overall survival (OS) one, she said, and the
improved PFS alone will not be enough to shift the drug to earlier lines of
treatment. At the same time, some oncologists may use the TERRAIN data to give
patients Xtandi instead of re-challenging with bicalutamide, but Xtandi and
Zytiga come with greater toxicity as well as higher costs, she noted.
However, after the FDA obtained approval in September
2014 based on the PREVAIL data, the use of Xtandi is not predicated on whether
a patient has received radium, Dendreon’s (OTCMKTS:DNDNQ) Provenge
(sipuleucel-T) or bicalutamide, said Dr. Robert Den, assistant professor,
radiation oncology and cancer biology, Sidney Kimmel Medical College, Thomas
Jefferson University, Philadelphia, Pennsylvania. It can be used once a patient
has documented metastatic CRPC, he added. Xtandi appears to be considered a
first-line treatment for mCRPC and is listed in the National Comprehensive
Cancer Network guidelines, Den said.
According to a 22 January press release,
TERRAIN’s median PFS was 15.7 months for Xtandi, versus 5.8 months for
bicalutamide. Serious adverse events respectively occurred in 31.3% and 23.3%
of Xtandi-treated and bicalutamide-treated patients, while Grade 3 or higher
cardiac events occurred in 5.5% and 2.1 % of patients treated with Xtandi and
bicalutamide, respectively. Two Xtandi patients had seizures, compared with one
bicalutamide patient.
Xtandi’s superiority over bicalutamide in
TERRAIN is not surprising, a Washington expert said, but superior PFS numbers
do not mean Xtandi should be used earlier in treatment because they do not mean
OS will be greater, and the results do not tell doctors anything about where in
treatment Xtandi belongs.
Yet, Den said PFS and toxicity numbers should
move Xtandi to earlier lines of treatment, nothing that National Comprehensive
Cancer Network guidelines list Xtandi, and the drug has shown a survival
advantage in earlier trials and adding that it appears to be already considered
a first-line treatment. In terms of toxicity, Den cited a need to wait for the
manuscript to understand the results, such as whether toxicity data reflects
Xtandi’s toxicity or TERRAIN’s low study population, he said. The toxicity
signals are not very different from other Phase III results, noted a Washington
state expert. Grade 3 or higher atrial fibrillation occurred in 2% of
Xtandi-treated patients in PREVAIL versus 1% in the placebo group.
Xtandi was approved in the pre-chemotherapy
setting in September 2014 based on data from the Phase III PREVAIL study
(NCT01212991).
However, the Washington state expert added she
prefers Provenge or radium and does not use bicalutamide anymore.
Testing Xtandi and Zytiga head-to-head would
give the best evidence for determining which should be used, Den said, though
greater experience with Zytiga drives its usage in Europe. But Xtandi is
preferable for diabetic patients because Zytiga requires combination with
prednisone, which adds toxicity for diabetics, Zhang and the Washington expert
said. However, the Washington expert added, Zytiga has lower seizure risk.
Data unlikely to sway PBMs
PBMs Express Scripts (NASDAQ:ESRX) and Eagen, Minnesota-based
Prime Therapeutics classify Xtandi as a Tier 5 drug, while Caremark (NYSE:CVS)
classifies it as a specialty drug requiring prior authorization, according to
the three largest PBMs’ most recent formularies.
However, the TERRAIN safety and efficacy data
is pretty weak and unlikely to move Xtandi higher within Tier 5, said John
Waddell, Consultant, TSM Associates, West Chester, Pennsylvania, noting the
study’s lack of OS data. The overall serious adverse event figures may not be
too big a deal given that the study was not highly powered, but the cardiac
toxicity is a red flag, he said. The cost differential is also a huge problem,
he added.
Notwithstanding varying criteria and
relationships with drug companies, PBMs may look at TERRAIN’s toxicity data and
decide generic bicalutamide is safer than Xtandi, said Harvey Arbit, professor,
Pharmaceutical Care and Health Systems, University of Minnesota College of
Pharmacy, Minneapolis. Cardiac toxicity is not only a serious side effect, but
a severe one, and such distinctions drive formulary decision making, he said.
In general, if there is a generic available in
the same class as a branded drug, PBMS may only choose to cover the generic,
Arbit noted. The Xtandi-bicalutamide situation may play out similarly to
Pfizer’s (NYSE:PFZ) Lipitor (atorvastatin) before it became generic in 2011,
when PBMs would only cover generic simvastatin, despite Lipitor’s greater
efficacy, requiring patients who still wanted Lipitor to pay out of pocket,
Arbit said.
If the Xtandi-bicalutamide price differential
is 10-20%, then PBMs may choose to cover Xtandi, but if Xtandi is several times
more expensive, they might not, said Stephen Schondelmeyer, professor,
Pharmaceutical Care and Health Systems, University of Minnesota College of
Pharmacy. Even a 10-month improvement in PFS may not be worth doubling the risk
of cardiac events for payers and PBMs, and those figures raise serious
questions about the safety and efficacy between the two drugs, let alone the
cost difference, he said, and they may question how Xtandi adds value.
Astellas’ market cap is JPY 4.4trn (USD
36.5bn). Medivation’s is USD 9.9bn.
Alaric DeArment
Reporter, New York
Alaric DeArment covers cancer drugs and
vaccines for BioPharm Insight. Previously, he was associate editor at Drug
Store News, covering retail and specialty pharmacy, pharmaceuticals, biologics
and regulatory affairs. A native of Seattle, he graduated with honors with a
bachelor degree in journalism from Ball State University and also lived in
China from 2001-2004.
Manasi Vaidya
Reporter, New York
Manasi Vaidya has a Master’s degree in
biotechnology. After a stint in a research lab, she spent two years as
correspondent in India for BioSpectrum, a publication focused on the Asian
biotechnology industry. She then moved to the United States to pursue a Master’s
degree in Science, Health and Environmental Reporting at New York University.
Manasi has reported primarily on topics that combine health and policy, and her
work has appeared in Nature Medicine, Nautilus and Scienceline. Her coverage at
BioPharm Insight focuses on cancer.