The Future of Prostate Cancer Care: Taking the Fight Early

Howard I. Scher, MD

The future of prostate cancer treatment will involve using biomarkers to identify which patients will respond to which medications and applying regimens currently in use for patients with advanced disease to men with earlier-stage disease, said Howard I. Scher, MD.

In a presentation at the 2018 LUGPA Annual Meeting, Scher, head of the Biomarker Development Initiative and the D. Wayne Calloway Chair in Urologic Oncology at Memorial Sloan Kettering Cancer Center, explained how “taking the fight early,” with an aggressive plan to cure patients with low-volume metastatic disease, would result in better outcomes. The hypothesis is that with the level of efficacy seen in castration-resistant disease, which is analogous to what physicians see in other cancers that can be cured even in the advanced setting, prostate cancer can be eliminated if those agents are employed earlier. 

“Why not take the fight early?” Scher said. “We have drugs that work in castration-resistant disease, and the question is: Can we develop a platform focused on eliminating all disease and getting patients down to a minimal tumor burden where the drugs are likely to have a chance to eliminate everything?”

Along with coprimary investigator Mary-Ellen Taplin, MD, director of clinical research with the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, Scher is conducting the multiarm METACURE trial (NCT03436654). The master trial explores multimodality therapy for patients with very-high-risk localized and low-volume prostatic adenocarcinoma to determine whether androgen suppression along with surgery and radiation can reduce the risk for recurrence.

Patients will receive 240 mg of daily apalutamide (Erleada) along with radical prostatectomy, extended pelvic lymphadenectomy, and physician’s choice of gonadotropin releasing hormone agonist/antagonist with or without 1000 mg of daily abiraterone acetate (Zytiga) and 5 mg of twice daily prednisone. Physicians will then stop therapy and look for testosterone recovery and prostate-specific antigen (PSA) level of zero.

The primary endpoint is the proportion of patients with pathologic complete response and minimal residual disease (tumor ≤5 mm). Secondary outcomes include PSA response rate and time to PSA progression.

Recruitment began in June 2018, and investigators hope to enroll 76 adult men. Patients will be segregated into 3 cohorts based on disease status.

Blood-Based Profiling for Second-Line Treatment Decisions

Physicians don’t yet know the optimal sequence in which to administer drugs. So, Scher said, they now are paying more attention to what was given and the sequence in which it was administered. But biopsies are necessary to understand changing biology, and there some challenges with those tests.

“If you do a bone biopsy, you have about a 50% chance of getting adequate tumor to profile,” he said. “The primary tumor, we know, is yesterday’s news and out of date, so ideally we’d like to work in blood tests.”

Scher focused on circulating tumor cells (CTCs), but there are a variety of tumor materials that can be assessed including circulating DNA, microRNA, exosomes, and microvesicles.

He noted that response to first-line abiraterone is not predictive for response to enzalutamide (Xtandi) in the second-line setting, creating an unmet need. Most patients, he added, will respond to treatment in the first-line, castration-resistant setting.

“But in the second-line setting, where you can’t predict how somebody is going to do with a androgen receptor— signaling inhibitior [ARSi] versus a taxane, that’s where the test starts to become informative,” Scher said.

In a study of a cross-sectional cohort, Scher and colleagues looked in the second-line or later setting for a particular predictive biomarker that would predict sensitivity to ARSis. They hypothesized that CTCs expressing a nuclear-specific AR-V7 protein could identify which patients with metastatic castration-resistant prostate cancer (mCRPC) would respond better to taxane therapy compared with ARSi.¹

From December 2012 to March 2015, investigators collected and processed 191 evaluable pretherapy blood samples from 161 patients with mCRPC. Thirty-four (18%) samples were positive for AR-V7 using nuclear-specific criteria and 56 (29%) were positive for AR-V7 using nuclear agnostic criteria.

At 12 weeks, none of the nuclear-specific AR-V7—positive samples (n = 16) showed ≥50% posttherapy PSA change following ARSi treatment compared with 19% (6/32) of nuclear-agnostic AR-V7–positive samples. Investigators found that the interaction between the presence of nuclear-specific AR-V7–positive CTCs and treatment with a taxane (hazard ratio, 0.24; 95% CI, 0.078-0.79;P= .019) was the strongest baseline factor influencing survival.

In contrast, AR-V7 localization agnostic scoring was not predictive of taxane benefit.

“We have drugs that work. I think this approach of taking the fight earlier, as is done in other diseases, will pay off, but we’re asking the question,” Scher said. “With advances in the blood-based diagnostics and positron emission tomography, we’re seeing the disease very differently.

Reference:

Scher HI, Graf RP, Schreiber NA, et al. Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic castration-resistant prostate cancer. Eur Urol. 2017;71(6):874-882. doi: 10.1016/j.eururo.2016.11.024.