(UroToday.com) In this presentation, David R. Wise, MD, PhD, reviewed three presentations in prostate cancer from this conference.
Abstract 5500 – TheraP: A randomized phase II trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel: Initial results (ANZUP protocol 1603)
Prostate cancers express the PSMA molecule on their surface, which has been exploited for targeted therapy. Prior clinical data has shown that the 177Lu-PSMA-617 molecule (LuPSMA), which delivers beta radiation to target cells causing cell death, has encouraging clinical activity from non-randomized studies in mCRPC. Specifically, a phase II study showed 64% of men experienced a 50% reduction in PSA on treatment, with relatively low toxicity. This abstract presented the first randomized study of LuPSMA relative to the standard of care option cabazitaxel in mCRPC. The primary endpoint was the rate of patients experiencing a decrease in PSA by 50%. Secondary endpoints were PSA progression-free survival and adverse events.
The study design is shown below. In total 98 patients were treated with LuPSMA and 85 patients were treated with cabazitaxel.
The study met its primary endpoint of demonstrating improved rates of 50% reduction in PSA relative to cabazitaxel. There was a 29% absolute improvement in this rate, and a 23% improvement after planned sensitivity analysis given patient dropout.
PSA progression-free survival data have not met criteria to reject the null hypothesis as of this presentation. The most common side-effects from LuPSMA therapy were thrombocytopenia, dry eyes and dry mouth. The most common Grade 3 or 4 toxicity was thrombocytopenia.
Dr. Wise suggested that this is a promising therapeutic modality that requires additional data including the quality of life, radiographic progression-free survival and overall survival results from this study, as well as results of the phase III VISION trial comparing LuPSMA to standard of care.
Abstract 5501 – Impact of PSMA-targeted imaging with 18F-DCFPyL-PET/CT on clinical management of patients (pts) with biochemically recurrent (BCR) prostate cancer (PCa): Results from a phase III, prospective, multicenter study (CONDOR)
18F-DCFPyL is a PSMA-targeting PET radiopharmaceutical under development for prostate cancer imaging. It is a lysine-linked, urea-based small molecule that is specific for prostate cancer cells. The agent is administered as a bolus injection, then PET imaging is performed 1-2 hours after administration.
In this abstract, the authors presented data from the CONDOR trial, a prospective study designed with the FDA to demonstrate the diagnostic performance of this imaging modality in the context of rising PSA after definitive therapy for localized disease where other imaging modalities fail to identify sites of disease recurrence. The primary endpoint is defined as lower 95% confidence interval of the correct localization rate > 20%. The correct localization rate (CLR) is essentially the positive predictive value for identifying a recurrence site. Imaging findings were compared to a composite standard of truth based on either evaluable histopathology, conventional imaging or confirmed PSA response after radiotherapy targeting the presumed site of recurrence. The secondary endpoint was the rate of change in treatment plans based on this imaging modality.
Importantly for this study, the median PSA value was 0.8 (range 0.17-98.45). 68.8% of patients had PSA < 2.0 ng/mL, and 14.9% of patients had PSA >= 5.0.
With regards to the primary endpoint, the study met its goal with all three independent radiology evaluators have a composite localization rate of >85%
64% of evaluated subjects had a change in therapeutic management after 18F-DCFPyL scan. Only 3 patients had an adverse safety event, with 1 out of 208 patients experiencing a hypersensitivity reaction.
Dr. Wise concluded that based on this data, (1) 18F-DFCPyL is more sensitive for detection of recurrent prostate cancer than current standard imaging agents, (2) it has a positive predictive value approaching 85% or greater, and (3) with further positive investigation of this agent, this imaging modality may be a highly accurate diagnostic agent for biochemically recurrent prostate cancer.
Abstract 5602 – HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer
Data suggest that cardiovascular mortality is the leading cause of death in patients who have been diagnosed with prostate cancer. This has been attributed in part to cardiovascular side effects from androgen deprivation therapy (ADT). There are two major mechanisms of ADT, designed to decrease serum testosterone to < 50 ng/dL and starve prostate cancer cells of the fuel necessary for growth. LHRH receptor agonists (leuprolide) provide constitutive stimulation and subsequent downregulation of GnRH receptors in the anterior pituitary gland. GnRH receptor antagonists directly block the function of these receptors in the pituitary. LHRH agonists are associated with a flare increase in FSH/LH production and subsequent testosterone levels such that they can cause a clinical flare. This necessitates the concomitant administration of androgen-receptor antagonists with therapy. GnRH antagonists do not have a flare phenomenon and may have an improved cardiovascular safety profile, but must be administered more frequently.
Regulolix is an oral GnRH antagonist administered daily. In this trial, the authors compared regulolix versus a three-month depot injection of the LHRH agonist leuprolide acetate in men with advanced prostate cancer. The primary endpoint of this study was to compare the number of patients with sustained castrate levels of testosterone after 48 weeks of therapy. The study design is shown below.
This study met its primary endpoint of non-inferiority of regulolix compared to leuprolide for sustained castration.
Importantly, patients who came off treatment with either agent had a quicker recovery of testosterone levels if treated with regulolix.
Finally, in an analysis of cardiovascular events, overall rates were higher in the leuprolide group relative to the regulolix group, especially in patients with a prior history of non-fatal myocardial infarction or non-fatal stroke.
Dr. Wise concluded that regulolix is an effective mechanism of inducing testosterone suppression and may be beneficial for patients who have a significant history of cardiovascular disease. He intends to use this drug for patients without GI absorption issues and with significant cardiovascular disease history. This will likely require more frequent testosterone checks as the medication is taken orally daily, increasing the risk of medication noncompliance.
Presented by: David R. Wise, MD, PhD, Assistant Professor of Medicine and Urology, Perlmutter Cancer Center and NYU Langone Health, New York, New York
Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.