Some men with prostate cancer may benefit from continued enzalutamide after progression
SAN FRANCISCO — Continued enzalutamide, after progression on the drug, in combination with docetaxel significantly extended PFS vs. placebo and docetaxel among men with metastatic castration-resistant prostate cancer, study results showed.
Enzalutamide (Xtandi; Astellas, Pfizer), an androgen receptor antagonist, plus docetaxel also demonstrated an acceptable safety profile in the randomized phase 3b PRESIDE trial.
Data derived from Merseburger AS, et al. Abstract 15. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.
“Enzalutamide is approved for the treatment of [metastatic hormone-sensitive] and castration-resistant prostate cancer, irrespective of metastases, and has been shown to significantly improve overall survival,” Axel S. Merseburger, MD, PhD, professor of urology and chairman of the department of urology at University Hospital Schleswig-Holstein in Lübeck, Germany, said during a presentation. “Preclinical and clinical studies have shown that the treatment sequence of enzalutamide followed by docetaxel limits the effectiveness of docetaxel; however, targeting the [androgen receptor] beyond progression may be of clinical benefit.”
The PRESIDE trial compared the efficacy of enzalutamide plus docetaxel and prednisone among chemotherapy-naive men with metastatic castration-resistant prostate cancer who progressed on enzalutamide.
The trial consisted of two periods. In the first period, 687 men received 160 mg enzalutamide (median duration of exposure, 62.2 weeks) plus ADT. Period 2 included 271 men who had a PSA response that represented a 50% or greater change from baseline to week 13 and later experienced progression. Those men received 75 mg/m2 docetaxel, 10 mg prednisone and ADT before being randomly assigned to 160 mg enzalutamide (median duration of exposure, 36.1 weeks) or placebo (median duration of exposure, 30.1 weeks).
The enzalutamide and placebo groups in period 2 had similar demographics and characteristics at baseline, including median age (71.5 years vs. 69 years) and baseline serum PSA level (median, 36.9 µg/L vs. 28.1 µg/L).
PFS in period 2 from randomization to radiographic/clinical progression or death served as the primary endpoint. Secondary endpoints included time to PSA progression, defined as a 25% or greater increase or absolute increase of 2 ng/mL, and PSA response in P2. Researchers recorded adverse events to evaluate safety.
All but two patients in period 2 had discontinued therapy by data cutoff, April 30, 2020, and about 75% in each group had progression. Results showed significant improvement in PFS with continued enzalutamide vs. placebo (HR = 0.72; 95% CI, 0.53-0.96). Men in the enzalutamide group had median PFS of 9.53 months (95% CI, 8.25-10.87) compared with 8.28 months (95% CI, 6.28-8.71) for those in the placebo group.
Researchers observed a consistent PFS benefit in post-hoc analyses of subgroups based on ECOG score, age, Gleason score, disease location, presence of visceral disease and baseline median PSA level.
“Of note, the largest benefit was observed in soft-tissue bone and visceral disease, suggesting that those aggressive tumors may benefit first from this therapy intensification in [metastatic castration-resistant prostate cancer],” Merseburger said.
Enzalutamide also delayed time to PSA progression significantly (8.44 months vs. 6.24 months; HR = 0.58; 95% CI, 0.41-0.82). By week 13, men in the enzalutamide group had a larger mean percentage decrease in PSA levels from baseline vs. the placebo group (37.12% vs. 9.11%).
Forty-six men (6.7%) in period 1 died and 20 died in period 2, including 13 (9.6%) in the enzalutamide group and seven (5.2%) in the placebo group. Similar proportions of men in the period 2 enzalutamide and placebo groups experienced a treatment-emergent adverse event of any grade (97.8% vs. 97%), of grade 3/grade 4 (61.8% and 62.2%) or that led to discontinuation (8.8% vs. 6.7%). The most common grade 4 treatment-related adverse event was neutropenia (16.9% vs. 20.7%). The groups also had similar rates of drug-related (46.3% vs. 41.5%) and docetaxel-related (90.4% for both) treatment-emergent adverse events.
“Altogether, the results suggest that continued treatment with enzalutamide plus docetaxel offers clinical benefit and could be a future treatment option for some men who progress on enzalutamide alone,” Merseburger said.
Perspective
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What are we going to do with a PFS endpoint? I don’t think here that OS is a planned endpoint. In all fairness, is OS achievable with all of those moving parts? Probably not. So how does one interpret this from a patient perspective?
A PFS endpoint has meaning and can have clinical benefit, and as long as the safety is there ... it still is quite important to recognize that the additional medication does not really worsen the toxicity.
So, the take-home message from this — other than congratulations, Dr. Merseburger, the team and the patients — is that he’s right. It’s a treatment option. Is it a standard of care? No. But would I be comfortable in knowing the patient has responded to enzalutamide, continues to have clinical benefit, but has some slight progression and may have some clinical benefit with an improvement in PFS of 28%, and offering that with docetaxel? Yes. Knowing your patient matters.
Perspective
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Treatment beyond progression is a key therapeutic paradigm in the management of advanced prostate cancer.
We continue castration therapy despite progression because we believe this contributes to cancer control. We continue abiraterone or enzalutamide beyond rising PSA until there is clinical or radiographic progression because this was believed to be part of the success seen in the registrational trials with these agents. However, once there is clear disease progression — enough to warrant initiation of chemotherapy — how would continuing androgen receptor-targeted therapy contribute? Synergy has not necessarily been documented for the combination, and no treatment has ever succeeded at improving outcomes when added to docetaxel in metastatic castration-resistant prostate cancer.
The PRESIDE study showed that continuing enzalutamide when starting docetaxel extended PFS compared with docetaxel plus placebo. However, although statistically significant, the clinical significance of delaying radiographic changes by a few weeks is unclear. Patients were considered to have disease progression by either PSA or radiographic progression, and we have not seen the breakdown of how many patients qualified for period 2 based on PSA alone. That said, there was not much added toxicity. So, the main cost would be financial. And the fact that PSA responses were greater with the combination lends some support to the possibility of synergy, or at least importance of tumor heterogeneity.
A physician may feel enzalutamide is contributing substantially to ongoing cancer control in select patients despite cancer progression, which is significant enough to warrant the addition of chemotherapy. But this approach should certainly not be applied across the board, given the modest benefit and uncertain impact on OS. Most importantly, physicians must remember to consider imaging results when making decisions to change treatment and should not base this decision on PSA alone.
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Merseburger AS, et al. Abstract 15. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.