6-month progression is strong survival surrogate in mHSPC

Disease progression within 6 months was the strongest surrogate marker for overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer treated with combination therapy in a retrospective analysis of the CHAARTED trial.

Although metastatic-free survival is a standard surrogate for OS in men with nonmetastatic prostate cancer, the best predictor of OS in the metastatic hormone-sensitive setting has not been established.

The data were presented in poster format at the American Urological Association 2020 Virtual Experience.

“We feel that this information has several important clinical implications,” coauthors John Pfail, MD candidate (class of 2021) at the Icahn School of Medicine at Mount Sinai Hospital in New York, New York, and Alberto Martini, MD, from Università Vita-Salute San Raffaele, in Milan, Italy, said via email. “First, it can be used for patient counseling for individuals who have progressed within the first 6 months of treatment. Second, it can be used for early identification of those individuals who might benefit from second-line treatments or might be enrolled in trials aimed at evaluating the role of novel therapies.”

In the CHAARTED trial, patients with metastatic hormone-sensitive prostate cancer were randomized to androgen-deprivation therapy (ADT) or ADT plus docetaxel. Response by prostate-specific antigen level, progression, and development of castration-resistant prostate cancer (CRPC) within 6 and 12 months were examined as a potential surrogate for OS in 790 patients from the study-393 who received ADT alone and 397 who received ADT plus docetaxel.

The investigators used the proportion-of-treatment effect (PTE) to measure how much of the OS outcome could be explained by the surrogate. The PTE is calculated from 2 proportional hazards models and is computed as 1 minus the ratio of the estimated regression coefficient for treatment effect in the adjusted model (model containing the surrogate) over the estimated regression coefficient for treatment in the unadjusted model.

“To the best of our knowledge, this method [PTE] is widely accepted in the scientific community and has been used in numerous analyses to validate potential surrogates,” according to the co-investigators, working under William K. Oh, MD, chief of the Division of Hematology and Medical Oncology at Mount Sinai Hospital.

Four intermediate clinical end points emerged as surrogates:

• Progression within 6 months (HR, 5.70; 95% CI, 4.26-7.64; P <.001)

• Progression within 12 months (HR, 7.09; 95% CI, 5.16-9.76; P <.001)

• Development of CRPC within 6 months (HR, 5.11; 95% CI, 3.81-6.85; P <.001)

• Development of CRPC within 12 months (HR, 6.24; 95% CI, 4.58-8.51; P <.001).

Of these, progression within 6 months had the highest PTE at 88%, followed by development of CRPC within 6 months (80%), progression within 12 months (52%), and development of CRPC within 12 months (46%).

“According to our analyses, progression within 6 months can identify almost 9 out of 10 men that will ultimately die from any cause,” according to the coinvestigators.

The 2-year OS rate for patients who progressed within 6 months of randomization was 42%, compared with 89% for the men who did not progress that quickly.

“According to our study, among the patients that were alive and not censored 6 months after randomization and did progress on treatment, the survival rate was almost one-fourth after 2 years. The prompt administration of second-line therapies or the exploration of novel medications for this patient category might potentially translate to a survival benefit for this patient population,” the coauthors indicated.

The study is the first to evaluate potential surrogates for metastatic hormone-sensitive prostate cancer and should be validated in other datasets, they added. “Nonetheless, if a novel medication determines an unprecedented response in terms of progression within 6 months from patient randomization, then regulatory agencies might consider expediting approval of such a medication,” they wrote.

Whether patients who progressed within 6 months from randomization did so because of an intrinsic resistance to docetaxel or the presence of a lethal phenotype due to specific genomic alterations, or a combination of both factors, is not known.

“It would be interesting to see if patients could be clustered from a genomic standpoint, according to the potential response within 6 months of therapy and use this eventual genomic classifier as a stratification factor in future trials,” the coinvestigators wrote.