Prospects and limits of chemotherapy in advanced metastatic PCa

Tue, 24 Apr 2012

The prospects and limits in using chemotherapy in managing advanced metastatic prostate cancer (PCa) were examined in the concluding session of the 9th ESOU Meeting. Prof. Susanne Osanto (NL) gave a comprehensive overview on chemotherapy for advanced, castration resistant prostate cancer (CRPC) saying that prostate cancer is usually still androgen-driven at the castration-resistant stage and is chemo-sensitive.

"However there are currently novel hormonal treatments that are effective following progression on ADT, and effective new bone-targeting agents," she said. Osanto mentioned that, historically, few chemotherapy drugs were licensed in the last 20 years such as estramustine in the 1980s, mitoxantrone, prednisone and samarium in the 1990s and, in the last decade, zoledronic acid in 2002 and docetaxel combined with prednisone in 2004, which provides prolonged overall survival compared with mitoxantrone plus prednisone.

“Docetaxel is the new CRPC standard since 2004,” added Osanto. Regarding current prospects, combination chemotherapy like in other cancer types has the potential, but one needs more than one active drug. A neo-adjuvant approach before radical prostatectomy is also indicated or as an adjuvant in high-risk cancer after radical prostatectomy. There may also be benefits of early use in newly diagnosed metastatic patients.

Cabazitaxel has also emerged as a new generation taxane with activity against tumor cells and models that are resistant to other taxanes. In Phase 1 trials, dose-limiting toxicity was neutropenia and activity in docetaxel-resistant mCRPC was observed, she explained.

Osanto also mentioned the TROPIC study which investigated cabizitaxel in second-line after docetaxel failure. Among the most frequent adverse events are febrile neutropenia, diarrhea, fatigue, asthenia and back pain among others. In the TROPIC study the main conclusions were:

• there is overall survival improvement compared with mitoxantrone;

• OS benefit is consistent among subgroups;

• the secondary endpoints of response rate and PSA support OS benefit; and

• the safety profile is predictable and manageable.

“Cabazitaxel is the first chemotherapy shown to prolong survival after docetaxel in mCRPC, with FDA and EMEA approval… and there are also planned studies of head-to-head comparison with docetaxel and lower dose,” said Osanto. She also highlighted the EAU Guidelinbes which states that only metastatic CRPC should receive chemotherapy, and that patients should have a testosterone serum level of <50 ng.dL and a PSA serum level of > 2 ng/mL.

The EAU guidelines also recommend docetaxel (75 mg/m2 q 3 weeks) as the standard, and consider cabazotaxel and aberration as second-line. Moreover, second-line docetaxel can be offered to previously responding docetaxel-treated patients.

Osanto also addressed the question as to why chemotherapy is not effective in everyone, saying that even in other diseases most drugs don’t work since there are many sources of variability in drug response such as compliance, absorption, metabolism and elimination. Although a near-cliché observation these days, personalized medicine, according to Osanto, would characterise the landscape of treatment for mCRPC.

“But there is a need to identify driver pathways in cancer and find germline genetic markers for drug response. Moreover clinical trials have to be conducted in a timely fashion, with researchers needing to overcome bureaucratic hurdles,” she explained. Furthermore, there is the need to combine drugs and move the focus to an earlier stage of the disease aside from individualizing the treatment.

Querying whether there would be a “battle” or tug-of-war in CRPC treatment among the various oncology disciplines, Osanto said she hopes that there would instead be more effective collaboration among prostate cancer specialists as she noted that surgical options are still the most effective in CRPC therapy.