- First-mover advantage – Topline results will grant Xtandi a significant first-mover advantage of approximately two years over rival compounds in the underserved non-metastatic castration-resistant prostate cancer (CRPC) patient population.
- Label expansion – Xtandi will expand its patient coverage to all CRPC patients across the prostate cancer spectrum as the first androgen receptor inhibitor to show a statistically significant improvement in reducing disease progression in the non-metastatic setting in addition to ADT therapy.
- Revenue growth – If approved, the non-metastatic label will boost Pfizer and Astellas’s US Xtandi sales and help negate recent clinical disappointments.
Positive results from the Phase III PROSPER trial (ClinicalTrials.gov identifier: NCT02003924) will grant Pfizer and Astellas’s Xtandi (enzalutamide) a first-mover advantage in the significant non-metastatic prostate cancer setting. Xtandi is the first androgen receptor inhibitor to show a statistically significant improvement in reducing disease progression in the non-metastatic setting in addition to ADT therapy, and, if approved, this label will expand Xtandi’s coverage to all CRPC patients. However, sales growth will be tempered by existing widespread use of Xtandi off-label in the non-metastatic setting, and Pharmavitae Analytics forecasts US Xtandi sales for Pfizer and Astellas to increase by only approximately $300m and $260m, respectively, by 2026. Nevertheless, the PROSPER results will help combat competitive pressures on Xtandi, and relieve pressures on Pfizer and Astellas.
In the Phase III PROSPER trial investigating Xtandi in patients with non-metastatic CRPC, topline results show that the addition of Xtandi to androgen deprivation therapy (ADT) met its primary endpoint of improved metastasis-free survival versus ADT alone (Astellas, 2017). A significant population of non-metastatic patients continue to progress to metastatic disease, identified by a rising prostate-specific antigen (PSA) level despite ADT. These data represent a significant breakthrough by demonstrating Xtandi to be the first androgen receptor inhibitor to show a statistically significant improvement in reducing disease progression in the non-metastatic setting in addition to ADT therapy. Assuming confirmation of this effect in the full trial data and subsequent product launch, a label approval in the non-metastatic setting will significantly boost US Xtandi sales for partners Pfizer and Astellas, helping to regain market share lost to class rival Zytiga (abiraterone acetate; Johnson & Johnson/AstraZeneca) owing to developmental setbacks.
First-mover advantage in non-metastatic CRPC patients
- First-mover advantage – These topline results grant Xtandi a significant first-mover advantage of around two years over Johnson & Johnson’s Zytiga, and open the use of androgen receptor inhibitors as a maintenance therapy in addition to ADT in the non-metastatic setting.
- Expanded patient pool – The trial results were accelerated to extend this advantage in the non-metastatic segment, and capitalize on longer therapy durations in this large untapped patient population. This will expand anti-androgen treatment across the prostate cancer spectrum, and significantly broadens Xtandi’s label and commercial potential.
- Pfizer – This is a key R&D win for Pfizer, which acquired Medivation and access to Xtandi in 2016 for $14bn, and had pinned Xtandi as a key growth driver for the future.
- Astellas – For Astellas, the drug is its largest grossing product, and Pharmavitae Analytics forecasts Xtandi’s annual sales attributable to the company to grow by $1.7bn from 2016 to 2026, supplemented by an approval in non-metastatic CRPC. Pfizer and Astellas are expected to file Xtandi for regulatory approval in this label by the end of 2017.
Off-label use in non-metastatic CRPC will temper sales boost
The sales boost for Xtandi will be tempered by off-label use currently experienced in the non-metastatic CRPC patient segment:
- Datamonitor Healthcare’s primary research survey shows that both Xtandi and Zytiga have seen strong uptake in this market segment, despite being indicated only for metastatic CRPC patients. This is because there is no approved therapy specifically for the non-metastatic CRPC population, and is also due to the proven efficacy of these therapies in more advanced patients.
- This off-label use will limit the sales boost due to the label expansion, and subsequently Pharmavitae Analytics forecasts US Xtandi sales for Pfizer and Astellas to increase by approximately $300m and $260m, respectively, by 2026. Drugs looking to enter the non-metastatic CRPC setting will be compared to standard ADT, which is relatively inexpensive compared to newer anti-androgens.
- Many other companies are also pursuing approvals in the non-metastatic market, and will be disadvantaged by the Xtandi breakthrough. Other Phase III drugs include Johnson & Johnson’s JNJ-56021927 (apalutamide) and Bayer/Orion’s darolutamide. The current high levels of off-label use of Xtandi and the early trial completion in the non-metastatic CRPC setting will mean it will have a significant head start over pipeline competitors.
Protocol adjustments risk pays off
Pfizer and Astellas’s risk to adjust the PROSPER study protocol has been a success, as the interim results hitting the efficacy endpoint will accelerate approval by around two years. The PROSPER study was originally designed to enroll 1,560 patients with non-metastatic CRPC, but in June 2017 the companies tweaked the study protocol to reduce the sample size to 1,440, despite the risk of underpowering the study and trial failure. Fortunately, the risk appears to have paid off for the companies, and interim results, originally set for June 2019, will position Xtandi approximately two years ahead of Zytiga in the pre-metastatic market, while the non-metastatic label will boost US Xtandi sales. However, it must be considered that the PROSPER trial results are only provisional, and Xtandi will need to demonstrate a clear numerical improvement in disease progression in the full PROSPER trial results to be routinely prescribed.
PROSPER results will relieve competitive pressures on Xtandi
The PROSPER trial results will help provide relief following competitive pressures and development setbacks that have limited Xtandi’s revenue growth in the US, with patient segments being ceded to rival Zytiga, and Xtandi’s net sales declining by 11% in Q1 2017.
- Lost ground in hormone-naïve CRPC patients – Xtandi has lost market share to Zytiga and the opportunity for first-mover advantage in the hormone-naïve metastatic CRPC patient population. Results from the LATITUDE study (ClinicalTrials.gov identifier: NCT01715285) in June 2017 showed that Zytiga was effective in the high-risk hormone-naïve population of metastatic CRPC patients in combination with ADT.
- PLATO trial failure – In December 2016, the Phase IV PLATO study (ClinicalTrials.gov identifier: NCT01995513) failed to show that continued treatment with Xtandi plus Zytiga and prednisone compared to Zytiga and prednisone alone showed an additional improvement in PFS in chemotherapy-naïve metastatic CRPC patients.
- Breast cancer – The decision to discontinue Xtandi’s development in triple-negative breast cancer had intensified pressure for the drug to succeed in prostate cancer.
Astellas (2017) Pfizer and Astellas Announce Positive Top-Line Results from Phase 3 PROSPER Trial of XTANDI (enzalutamide) in Patients with Non-Metastatic Castration-Resistant Prostate Cancer. Available from: https://www.astellas.com/en/corporate/news/pdf/170914_1_Eg.pdf [Accessed 14 September 2017]