Astellas/Medivation's Xtandi Has Questionable Potential to Displace Bicalutamide

Astellas (TYO:4503)/Medivation's (NASDAQ:MDVN) 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 May not be sufficient to justify moving drug to earlier therapy lines

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 ClinicalTrials.gov.

iThe 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.

Generic competitor, greater toxicity may discourage PBM coverage

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 31.1% and 23.3% of Xtandi-treated and bicalutamide-treated patients, while Grade 3 or higher cardiac events in 5.5% and 2.1% of patients treated with Xtandi and bicalutamide, respectively. Two Xtandi patients had seizures, compared with one bicalutamide patient.

Xtnadi'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 occured 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 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 availability 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.

April 6, 2015

Alaric DeArment

Reporter, New York

Alaric DeArment covers cancer drugs and vaccines for BioPharma 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 Masters 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 Masters 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.