Novel Agent Being Explored in Two Trials of High-Risk Prostate Cancer

Patients with high-risk, localized or locally advanced prostate cancer who are receiving primary radiation therapy will hopefully demonstrate an improvement in metastasis-free survival on the late-stage efficacy and safety of apalutamide (ARN-509), according to the global principal investigator, Howard M. Sandler.

“The patient population that we’re studying are men who are at risk of dying of prostate cancer,” Sandler, chair of the Department of Radiation Oncology at Cedars-Sinai Medical Center in Los Angeles, told CURE. “If we can provide better upfront disease control, we’re hoping to reduce the number of men who enter into the castrate-resistant prostate cancer stage.”

The ATLAS trial (NCT02531516; learn more here) was launched in February 2016. After screening and randomization, patients in the treatment arm of the study will receive apalutamide (240 mg) daily for 28 months, gonadotropin-releasing hormone (GnRH) for 28 months and radiation therapy (74-80 Gy) to the prostate gland started at about eight weeks after randomization. Patients in the control arm will receive Casodex (bicalutamide) (50 mg) for four months, apalutamide placebo and GnRH for 28 months and radiation therapy. Apalutamide is a novel small-molecule androgen receptor (AR) antagonist similar to enzalutamide but with less central nervous system penetration, which could potentially result in reduced levels of fatigue and seizures.

The agent binds to AR in target tissues, thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus.

This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells.

Researchers have found that the combination of different forms of androgen deprivation therapy (ADT) and radiation has been beneficial, with long-term administration of ADT resulting in better outcomes than short-term administration.

Results from a study presented at the American Society for Radiation Oncology showed that continuation of ADT for an additional two years improves all disease-specific endpoints during 15 years of follow-up compared with short-term ADT in men with locally advanced prostate cancer treated with radiotherapy.

Although there have been important developments for patients with metastatic castration-resistant prostate cancer (CRPC), many patients will not have metastatic disease (M0) when castration resistance develops.

Non-metastatic CRPC is often detected biochemically, through a rise in prostate-specific antigen (PSA) levels in men who are currently taking ADT. It remains unknown how to optimally treat this population since the standards of care for metastatic disease do not apply to these individuals. Prevention of metastases is a major unmet medical need for patients with M0-CRPC.

Sandler said the treatment phase of the ATLAS trial consists of 28-day cycles and includes 30 months of continuous hormonal therapy with radiation therapy.

The primary endpoint is metastasis-free survival that is assessed by imaging. “But we won’t start imaging until we see a rise in PSA level,” said Sandler. Long-term follow up will continue until death.

Four secondary endpoints include time to local-regional recurrence, time to CRPC, time to distant metastasis, and overall survival (OS). ATLAS is expected to fully enroll 1,500 patients by 2020 with a study completion date in 2026.

“Radiation is a commonly used treatment modality for prostate cancer. Radiation plus hormonal therapy is a well-established treatment paradigm. Enhancing both the radiation component and enhancing the hormonal component are likely to lead to better outcomes for high-risk prostate cancer,” Sandler said.

Prostate cancer is the second most common cause of cancer-related deaths in American men (26,120 estimated deaths in 2016). Treatment of localized tumors is often curative; however, 10 percent to 20 percent of patients diagnosed with prostate cancer develop CRPC within five years of follow-up and more than 30 percent of these patients go on to develop metastates. The disease is initially sensitive to ADTs (castration- sensitive disease state), but resistance is inevitably acquired, leading to CRPC that is incurable.

Despite administration of androgen-depleting therapies, continued AR signaling is a common feature of CRPC, attributed to AR gene amplification or mutation, increased AR expression, or increased androgen biosynthesis in prostate tumors. Apalutamide also is being explored in the phase 3 SPARTAN study (NCT01946204; learn more here). For SPARTAN, eligible patients must show no signs of evident metastatic prostate cancer and must have either a high risk for disease progression, defined as a PSA doubling time (PSADT) of less than 10 months while on continuous ADT, or CRPC demonstrated while on continuous ADT. PSADT is calculated using at least three PSA values during ADT.

It is expected that SPARTAN will enroll 1,200 patients by late 2016. Final results can be expected in 2019. Patients are expected to be followed for up to five years, with a primary endpoint of metastasis-free survival and numerous secondary endpoints including OS, time to symptomatic progression, time to initiation of chemotherapy, progression-free survival and time to evidence of metastasis.