Consider Clinically Relevant Novel Endpoint at Earlier Disease Stage To Change Outcome of More Patients

March 23, 2018 Suzanne Konigsberg

Bob Desai, Vice President-Technical, Partha Roy, Vice President -Technical, Bruce Babbitt, Vice President-Technical, PAREXEL Consulting

Traditionally cancer drug approval has been based predominantly on direct effects on the tumor (response rates) or patient survival (progression free survival, disease free survival or overall survival); however, in certain cancers, for example, men with prostate cancer, tumor metastases are a major cause of complications and death. Nearly all men who die from prostate cancer have antecedent metastases to bone or other sites, including the lymph nodes, lung, and liver1. Bone metastases are associated with pain, pathologic fractures, and spinal cord compression1. Therefore, prevention of metastases to the bone and other sites represents an important treatment goal.

The US FDA recent approval of Erleada (apalutamide) for treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) and similar reports of Pfizer’s enzalutamide using same primary end-point2 as well Bayer’s ongoing study of darolutamide3suggests that FDA had few concerns with the pivotal trial's novel primary endpoint of metastases free survival.  "This approval is the first to use the endpoint of metastasis-free survival," FDA Oncology Center of Excellence Director Richard Pazdur emphasized in the agency's Feb. 14 announcement on the approval. "This demonstrates the agency’s commitment to using novel endpoints to expedite important therapies to the American public 4." This position by the US FDA is consistent with the promise on 21st Century cures Act passed by the Congress  in Dec, 2016.

The Erleada Phase III trial, known as SPARTAN, defined metastasis-free survival (MFS) as "the time from randomization to the time of first evidence of [blinded independent central review]-confirmed distant metastasis, defined as new bone or soft tissue lesions or enlarged lymph nodes above the iliac bifurcation, or death due to any cause, whichever occurred first," labeling summarizes.

SPARTAN enrolled 1,207 prostate cancer patients who no longer responded to medical or surgical treatments to lower testosterone but who had no evidence of metastasis. Disease progression is a high risk for such patients; J&J reports that 90% of patients with non-metastatic CRPC will eventually develop bone metastases. All patients in the trial received androgen deprivation therapy (ADT) along with either once-daily oral Erleada or placebo. Median MFS for Erleada patients was 40.5 months, compared with 16.2 months on the placebo. "The major efficacy outcome was supported by statistically significant improvements in TTM [time to metastasis], PFS [progression-free survival], and time to symptomatic progression," labeling adds. Overall survival data were not mature and likely not considered as part of clinical evidence for this regular approval. In addition, similar to concern related to other anti-androgen novel agents Erleada labeling urges prescribers to "evaluate patients for fracture and fall risk." Falls were reported by 16% of Erleada patients in SPARTAN, compared with 9% of placebo patients. Fractures were seen in 12% of patients on Erleada and 7% of the placebo arm. Labeling also includes seizures under Warnings and Precautions, noting a 0.2% incidence with Erleada vs. zero for placebo5,6.

Many cancers can have limited impact on patient’s life, when detected early with routine screening and can be treated with local treatment/s such as surgery and/or radiation as long as patient remains metastases free.

The traditional development pathway of developing new oncology drug at later stage of disease such as for metastases stage ( which almost invariable is incurable and impact on long term survival as patient’s quality of life is less compared to treating them prior to metastases development), may need to change for those cancers which can be detected early by routine screening. Focusing on early stage of cancer disease for innovative oncology drug development as priority for these cancers will benefit many more patients with impact likely more compared to developing innovative oncology therapeutics for metastatic cancer.


  1. Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. PLoS One 2015;10(10): e0139440
  6. Erleada, US, label


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