ORLANDO, FL, USA (UroToday.com) - To say that we are excited about these new drugs for castrate-resistant prostate cancer (CRPC) patients is an understatement,” commented Charles Ryan, MD (UCSF), “Yet there are patients who will not respond to these new therapies, we need to know why and how to course correct their treatment plan.”
He presented several clinical scenarios to medical oncologists and urologists at the 2013 ASCO Genitourinary Cancers Symposium. A by-product of using abiraterone acetate (AA) or enzalutamide (Enz) is the development of AA- and/or Enz-refractory CRPC. Dr. Ryan described several clinical scenarios and suggests clinical trial design strategies to enhance therapy options.
There are mixed definitions of what constitutes progression in CRPC. Scenario #1: Non-progression is defined when the patient experiences an event consistent with disease progression but has not met the criteria for clinically significant disease progression (For example, rise in PSA without radiographic progression or the patient with a bone scan flare). Clinical strategy: Studies should evaluate the clinical benefit of AA or Enz following PSA progression to the point of symptomatic or radiographic progression. These types of trials would require PSA + radiographic progression to confirm progressive disease.
Scenario #2: Primary resistance, defined as the lack of clinically significant response to a given agent, relates to the patient that fails to produce a drop in PSA or an objective response within the 12-week benchmark. Clinical strategy: Of the approximately 30% of patients treated with AA or Enz who experience primary resistance, consider a tumor that is dependent on a non-AR-directed mechanism (for example, c-met). These patients have likely developed pharmacodynamic resistance. Using a combination approach of AA or Enz may have limited value.
Scenario #3: Phenotypic change means a nonadenocarcinoma has emerged from the prostatic adenocarcinoma. While rare but lethal, a clone may appear from the neuroendocrine tumor cells during the time the tumor is suppressed by the androgen receptor. If the PSA is low or zero, take a biospy looking for a change in the anaplastic form. Clinical strategy: Consider platinum-based chemotherapy. Biopsy material should be evaluated if other phenotype changes are occurring (not pure small cells).
Scenario #4: Acquired resistance, the most common scenario, is defined as the emergence of progressive disease following a period of response to a single agent (AA or Enz). The acquired resistance takes one of two forms: adaptive resistance (selection of Pi3Kinase mutated tumors); or compensatory resistance (upregulation of CYP17 to overcome inhibition). In this scenario, the tumor appears to adopt accessory pathways to proliferate and enhance survival. Ongoing studies at UCSF are targeting mechanisms of resistance using a two-step trial design. In one arm, patients are treated with abiraterone in the chemotherapy-naïve setting (including PSA response and scans). In this study, at the time of PSA progression, the abiraterone will be increased to 2 000 mg daily. The study aims to determine if higher doses will reinduce a reduction in the PSA, thereby extending the duration of the drug. In a second study at UCSF, investigators are exploring dual targeting of Pi2Kinase with BEZ-235 (Novartis). They hypothesize that PSA response is proportional to, and will be higher, in patients treated with combination therapies rather than monotherapy. Dr. Ryan commented, “It’s likely adaptive resistance will require new drugs, whereas, compensatory resistance may benefit by optimizing existing therapies.”
As a wrap up, Dr. Ryan made the observation, as an investigator on several clinical trials, of a trend among prostate cancer patients. “If they (the patients) have to contribute $30 or more out of pocket to their ongoing treatments, they tend not to be as compliant (missing appointments and creating gaps in the continuity of care) in order to possibly skip a dose to save money. This social-economic observation should be validated along with ongoing studies regarding sequencing, dosing, etc. The rationale for sequencing strategies exists, but we just need to test them.”
Highlights of a presentation by Charles J. Ryan, MD at the 2013 Genitourinary Cancers Symposium - February 14 - 16, 2013 - Rosen Shingle Creek - Orlando, Florida USA
UCSF, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
Written by Karen Roberts, medical editor for UroToday.com.
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