Hoping to give blockbuster prostate cancer drug Xtandi one more boost before it falls off the patent cliff, Astellas and Pfizer shared new data showing the androgen receptor inhibitor works in an earlier form of the tumor type.
Adding Xtandi to the hormone therapy leuprolide prevented tumor metastasis or death, lowering the risk by 58% compared with leuprolide alone in men with non-metastatic hormone-sensitive prostate cancer (nmHSPC). Xtandi alone led to a smaller but still statistically significant reduction of 37% on the same endpoint, the companies said.
Investigators presented the phase 3 data at the American Urological Association’s 2023 annual meeting. If approved, nmHSPC would be Xtandi’s fourth U.S. indication. Originally approved in 2012, Xtandi is currently used for all stages of castration-resistant prostate cancer and for metastatic hormone-sensitive disease.
nmHSPC occurs at an earlier stage in the course of prostate cancer. At this stage, patients still respond to traditional hormone therapy, and their tumors haven’t spread to other parts of the body. With the phase 3 Embark trial, Astellas and Pfizer targeted patients with high-risk biochemical recurrence, meaning they are more likely to develop metastatic disease.
Because nmHSPC is an earlier form of the disease, the Embark trial took a long time to read out. The two Xtandi regimens’ improvements in metastasis-free survival (MFS) were recorded after a median follow-up of six years, and none of the three treatment arms had reached their median MFS.
But the Xtandi combo helped 83.5% of patients go metastasis-free for at least five years, whereas leuprolide alone only did that for 71.4% of patients.
Xtandi also demonstrated a trend toward extending lives, although those data weren’t yet mature. The combo and the monotherapy reduced the risk of death by 41% and 23%, respectively, neither of which crossed the statistical significance bar.
The 1,068-patient trial has so far recorded 130 deaths, and the final overall survival analysis is planned at 271 deaths.
Having a favorable overall survival signal is important for a drug’s regulatory pathway in an early cancer setting such as nmHSPC. Lately, the FDA has been scrutinizing overall survival data—even if they are descriptive—to make sure new therapies don’t pose any potential harm to long-term outcomes.
Citing overall survival concerns, the FDA appears poised to deny AstraZeneca and Merck’s bid for a broad Lynparza approval in metastatic castration-resistant prostate cancer (mCRPC). An advisory committee on Friday sided with the agency, suggesting that a combination of the PARP inhibitor and Johnson & Johnson’s androgen receptor inhibitor Zytiga should only be approved in a small subset of patients with BRCA mutations.
For their part, Pfizer and Astellas plan to file Xtandi in nmHSPC this year, the two companies said Saturday.
Xtandi is Astellas’ cornerstone product and also a key cancer product at Pfizer. For the fiscal year that ended in March, Astellas booked 661 billion Japanese yen ($4.8 billion) of sales from Xtandi, good for 24% growth over the previous fiscal year, mainly thanks to international expansion. For its part, Pfizer recorded $1.2 billion in Xtandi collaboration revenue in 2022, a number that was flat year over year.
The star androgen receptor blocker is slated to lose U.S. patent protection in 2027, and Pfizer and Astellas are already fighting in court against generic contenders such as Sun Pharma and Zydus Pharma.
Meanwhile, hoping not to repeat the fate of Lynparza, Pfizer is readying Xtandi in a pairing with its own PARP inhibitor Talzenna. That combo also showed a tumor progression benefit in a broad mCRPC population that’s inclusive of patients with different gene alteration statuses. Overall survival data from the phase 3 TALAPRO-2 trial were immature, but the FDA will no doubt pick apart the study’s subgroup data.
The FDA has granted priority review to Pfizer’s application for the Talzenna-Xtandi combo in mCRPC and is expected to deliver a verdict this year.
In addition, Pfizer recently struck a $43 billion deal to acquire Seagen. The latter’s antibody-drug conjugate portfolio includes Merck & Co.-partnered ladiratuzumab vedotin, a LIV-1-targeted ADC that’s undergoing phase 2 trial in various solid tumors, including mCRPC.