The late-stage clinical pipeline for Prostate Cancer (CaP) is diverse and dynamic: news concerning three high-profile emerging agents in Phase III trials for CaP were released during September 2010.

  • On September 9th, Johnson & Johnson announced that the pivotal Phase III trial for abiraterone in chemotherapy-pretreated, metastatic, castrate-resistant CaP (MCRPC) was unblinded based on advice from the Independent Data Monitoring Committee (IDMC). There was a statistically significant improvement in overall survival (OS) in the pre-specified interim analysis.
  • On September 27th, AstraZeneca announced that zibotentan failed to significantly improve OS in a pivotal Phase III study in asymptomatic/minimally symptomatic MCRPC.
  • Finally, also on September 27th, Pfizer announced that the pivotal Phase III trial of Sutent in combination with prednisone for Taxotere-treated MCRPC patients has been discontinued because Sutent would unlikely improve OS.

Abiraterone is a highly promising emerging therapy for MCRPC. Decision Resources had forecasted a launch of abiraterone, the recent positive top-line OS results only confirm this agent is still on track to approval. Full data are not yet available but will be presented at the European Society for Medical Oncology (ESMO) conference next month. We forecast abiraterone will be a clinically and commercially successful agent in the treatment of MCRPC, but it also has potential to be used in earlier lines of treatment. Initially, abiraterone will be prescribed to MCRPC patients who have previously received chemotherapy, in this setting it will join Sanofi-Aventis newly FDA-approved chemotherapy, Jevtana (cabazitaxel). We forecast that abiraterone will also be approved in first-line asymptomatic/minimally symptomatic MCRPC, where it will compete with Dendreon's Provenge (sipuleucel-T) for patient share. It is unlikely these two agents will be used concurrently because of the chronic administration of prednisone (an immunosuppressive agent) (a requirement for abiraterone) may reduce the efficacy of Provenge. Oral delivery, proven mechanism of action, and likely lower cost of abiraterone compared with Provenge will help drive uptake of abiraterone in this setting.

Conversely, the failure of zibotentan in asymptomatic/minimally symptomatic MCRPC means zibotentan will not compete with Provenge or abiraterone. Decision Resources forecasted that zibotentan would not launch in this setting, however despite the recently announced failure, two further Phase III trials for zibotentan are ongoing in the ENTHUSE (Endothelin-A Use) clinical program. The failure of zibotentan to significantly improve OS in asymptomatic/minimally symptomatic MCRPC in Phase II and Phase III trials may be due to short treatment durations. Therefore, hope remains for zibotentan in non-metastatic CRPC (as a single agent) and in first-line MCRPC (in combination with Taxotere) because zibotentan will likely be given for extended durations.

Pfizer's pivotal Phase III trial for Sutent has been discontinued in the chemotherapy-pretreated MCRPC setting. The SUN-1120 trial was evaluating Sutent in combination with prednisone in Taxotere-pretreated MCRPC patients. The trial was discontinued based on advice from the IDMC because OS would unlikely be significantly improved. Decision Resources had forecasted that Sutent would not launch for MCRPC. The failure of Sutent follows in the wake of the March 2010 news that Roche/Genentech/Chugai's Avastin (bevacizumab) failed to significantly improve OS in first-line MCRPC setting in combination with Taxotere/prednisone. The failure of Sutent further highlights the questionable role of angiogenesis inhibition in the treatment of advanced CaP. Although high unmet need for improving OS in second-line MCRPC remains, cabazitaxel and now abiraterone will help fulfill this need. The failure of Sutent means that abiraterone and cabazitaxel can exploit this underserved population, and the anticipated entry of Medivation/Astellas Pharma's novel hormonal agent, MDV-3100, will also add to the therapeutic options in this setting.

The scale of abiraterone's positive OS results is eagerly anticipated. With ESMO just a few weeks away we will see the clinical impact of abiraterone in MCRPC and also learn of other clinical results that will shape the future CaP market.

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