ADT Plus Chemo Ideal for Oligometastatic Prostate Cancer

Bertrand Tombal, MD, PhD

Oligometastatic prostate cancer is optimally treated with the combination of docetaxel and androgen deprivation therapy (ADT), according to a presentation at the 7th European Multidisciplinary Meeting on Urological Cancers (EMUC).

“Oligometastatic disease is a transit state of prostate cancer and is an imaging technique-dependent definition,” Bertrand Tombal MD, PhD, Chairman of the Division of Urology, Universite Catholique de Louvain, Brussels, Belgium, explained at the conference. “Nevertheless, it is unlikely that metastases targeted treatment will be enough to control the disease.”

While tumor directed radiotherapy is effective in shrinking individual masses, Tombal underscored that systemic treatment was necessary for disease control. Traditional systemic options for prostate cancer include luteinizing hormone-releasing hormone (LHRH) agonists plus flare control or LHRH antagonists, maximized ADT, complete androgen blockade, and chemotherapy.

To further illuminate an effective treatment for oligometastatic disease, Tombal examined the results obtained in the CHAARTED, GETUG-15, and STAMPEDE trials of ADT plus docetaxel. The CHAARTED and STAMPEDE trials showed improved overall survival (OS) with the combination of ADT and docetaxel compared with ADT alone, especially in high-volume disease. However, the findings of GETUG-15 were less clear.

In a subanalysis of the STAMPEDE trial, the addition of docetaxel to standard of care ADT improved outcomes in patients with M1 hormone-naïve prostate cancer. In this group specifically, the median OS with docetaxel and ADT was 65 months compared with 43 months with ADT alone (HR, 0.73; P = .002).

In a combined analysis of 2993 men participating in the CHAARTED, GETUG-15, and STAMPEDE trials with M1 hormone-naïve prostate cancer, there was a marked improvement in OS with docetaxel (HR, 0.77; P < .0001). This benefit equated to a 10% absolute improvement in survival with the addition of docetaxel at 4 years.

In addition to adding chemotherapy, Tombal stressed that androgen receptor (AR) suppression could be improved. “But it is likely that it won’t be enough,” he said. “So the reference should be ADT plus 6 cycles of docetaxel whenever metastases are identified.”

To inform various ADT strategies, a meta-analysis of 21 trials was conducted across 6871 patients with various stages of prostate cancer. Overall, there was not a significant improvement in 2-year survival demonstrated between complete androgen blockade (LHRH agonist plus bicalutamide) compared with LHRH monotherapy (P =.8333).

However, Tombal noted, the effect of complete androgen blockade could be stage-dependent, since in the same study patients with stage III/IV disease achieved significantly improved OS with complete androgen blockade over LHRH alone (P = .0041).

Complete androgen blockade is currently being investigated in at least four ongoing phase III studies of new AR pathway inhibitors. These newer strategies look to further lower testosterone levels, which is a main driver of prostate cancer from the primary to the metastatic state. These studies are exploring ADT plus enzalutamide, abiraterone acetate, radiation therapy, and other therapies.

Whether one type of ADT is superior to another also remains a topic of investigation. Newer agents are showing promising findings, with a phase II study showing strong long-term results for enzalutamide monotherapy in patients with hormone-naïve prostate cancer (Tombal et al; Eur Urol. 2015;18(5):787-794). However, testosterone flare is a concern with non-steroidal antiandrogen agents.

Several reports have recently shown better PSA control with degarelix, a gonadotrophin-releasing hormone (GnRH) antagonist. In the phase III CS21 study, PSA and testosterone decreased steadily with degarelix over a 56-day period while initial surges in testosterone levels occurred within the first week with leuprolide.

An analysis of pooled data from 5 trials of degarelix versus LHRH agonists showed better PSA-specific progression-free survival (PFS) in the degarelix group (HR, 0.71; P = .017). The PSA-free PFS duration was 320 days with degarelix versus 280 days with an LHRH agonist.

For those with baseline PSA levels >20 ng/mL, the hazard ratio was 0.74 in favor of degarelix (P = .052). Additionally, overall survival (OS) was higher in the degarelix arm (HR, 0.47; P = .023).

Other findings showed a higher percentage of patients achieved testosterone levels <50 ng/mL by week one with the oral GnRH antagonist TAK-385 compared with leuporelin. The trial also showed that early PSA responses follow testosterone levels.

After 4 weeks, 84% of patients in the TAK-385 groups had PSA reduction of ≥50% compared with 31% in the leuporelin group. Also, 12% of TAK-385 patients had a PSA reduction of ≥90% versus none with leuprolide.