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Enzalutamide extended OS, PFS in chemotherapy-naive prostate cancer
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Treatment with enzalutamide significantly extended OS and radiographic PFS in chemotherapy-naive men with metastatic castration-resistant prostate cancer compared with placebo, according to study results presented at the 2014 Genitourinary Cancers Symposium.
“The radiographic PFS and time-to-chemotherapy results are quite striking in this trial and represent the direct effect of therapy that’s not contaminated by subsequent treatments post-progression,” Tomasz M. Beer, MD, FACP, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, said during a press conference. “The OS certainly is reassuring, but it incorporates into outcome the effects of subsequent therapy that these patients received.”
Tomasz M. Beer
Previous research indicated enzalutamide (Xtandi, Astellas Pharma) improved OS in men with metastatic castration-resistant prostate cancer who had received prior treatment with docetaxel.
In the double blind, phase 3 PREVAIL trial, Beer and colleagues sought to evaluate the agent in asymptomatic or mildly symptomatic men who had not received chemotherapy. They assigned 1,717 patients 1:1 to 160 mg enzalutamide daily or placebo.
Researchers conducted an interim analysis after 539 deaths occurred. At the time of analysis, more patients assigned placebo had died (35% vs. 28%).
Results showed enzalutamide was associated with a 30% reduction in the risk for death (HR=0.7; 95% CI, 0.59-0.83) and an 81% reduction in the risk for radiographic progression or death (HR=0.19; 95% CI, 0.15-0.23).
The estimated median OS in the enzalutamide arm was 32.4 months (95% CI, 31.5-upper limit not yet reached) compared with 30.2 months (95% CI, 28-upper limit not yet reached) in the placebo arm.
Median radiographic PFS had not yet been reached at the time of the analysis in the enzalutamide arm (95% CI, 13.8-upper limit not yet reached) but was 3.9 months (95% CI, 3.7-5.4 ) in the placebo arm.
Fifty-nine percent of patients assigned enzalutamide responded to treatment (complete response, 20%; partial response, 39%) compared with 5% of patients assigned placebo.
Researchers observed a 65%, or 17-month, increase in time to chemotherapy among patients who received enzalutamide compared with placebo.
The most common adverse events associated with treatment were fatigue, constipation, and back and joint pain. Two patients with a prior history of seizures — one from each arm — experienced seizure events.
“The concern was that, as we moved the drug into earlier disease states — like we did in this clinical trial — and as the duration of therapy lengthens, that some might see a higher rate of side effects, including seizures,” Beer said. “But the rate is actually lower than what we would have expected. With appropriate patient selection, this drug can be administered very safely from the perspective of seizure risk.”
Six percent of patients in both arms discontinued treatment due to adverse events.
The next step is to evaluate possible sequences and combinations of therapies, such as with abiraterone acetate (Zytiga, Janssen Biotech), Beer said.
“We have two new drugs — enzalutamide and abiraterone — that have emerged very rapidly and have been studied in phase 3 studies only in metastatic, advanced disease, and only in isolation from one another,” Beer said. “What these studies say is that not only do we have new treatment options, but they validate the notion that the hormonal signaling pathway is critically important in the management of prostate cancer. When you get new effective drugs in a disease, the work just begins. I think you’re going to see a continued evolution of how these drugs are used.”
For more information:
Beer TM. Abstract #LBA1. Presented at: 2014 Genitourinary Cancers Symposium; Jan. 30-Feb. 1, 2014; San Francisco.
Disclosure: Beer reports research funding from Astellas Pharma, Cougar Biotechnology, Janssen Biotech and Medivation. See the study for a full list of the researchers’ relevant financial disclosures.
Perspective
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Charles J. Ryan, MD
Enzalutamide is a drug that is currently available, but the current indication is for patients who have already received chemotherapy for prostate cancer. This study very importantly outlines the benefits associated with it in patients who have not yet had chemotherapy. This is an interim analysis ... [and] the numbers in terms of OS are likely to change with subsequent analyses, but this is an important study for our field ... and may expand the regulatory approval of enzalutamide.
One key factor is that, although chemotherapy is held up as the benchmark for this disease, the reality is that our current data suggest fewer than 50% of men with castration-resistant prostate cancer actually receive chemotherapy. This treatment, should the FDA change the regulatory status of enzalutamide, would open up this possibility of therapy for a very large population of patients who currently only have one or two treatment options available to them.
Perspective
Back to TopDonald L. Trump, MD
Fossa and colleagues report an updated analysis of the outcome of the study by The Scandinavian Prostate Group in which 875 patients with locally advanced or histologically aggressive prostate cancer with clinically localized disease were randomly assigned to 3 months of total androgen deprivation followed by prostate irradiation and continuous anti-androgen therapy (n=436) vs. continuous anti-androgen therapy (n=439).
Eligibility criteria are important to emphasize and, as outlined in the initial report of this study, included age younger than 76 years, good performance status, a life expectancy of more than 10 years, PSA ≤70 ng/mL and with no evidence of metastases. All participants were categorized as clinical T1b-T2, G2-G3 or T3, with any WHO grade 1-3. Those with PSA ≥11 ng/mL had pelvic lymph node dissection, and those with nodal disease were excluded (Widmark A. Lancet. 2009;373:301–308).
In the previous report, at a median follow-up of 7.6 years, those assigned to total androgen deprivation followed by prostate irradiation experienced a 12% reduction in prostate cancer-specific mortality compared to those assigned to continuous anti-androgen therapy.
In this report, follow-up is updated at 10 and 15 years. Prostate cancer death continued to occur less often in the total androgen deprivation followed by prostate irradiation group compared with the continuous antiandrogen therapy group. Deaths from all causes were also reduced in the total androgen deprivation plus prostate irradiation group. Prostate cancer and all-cause mortality were reduced significantly at 10 and 15 years. Interestingly, deaths from any cause were more frequent in the total androgen deprivation and prostate irradiation group compared with the continuous anti-androgen therapy group (116 vs. 92). Significance, or lack thereof, of this difference was not reported in the abstract.
These continue to be intriguing data, and not what many (including this reviewer) predicted, emphasizing once again the need to do clinical trials. Among men with localized prostate cancer, fulfilling the criteria specified in this study — in which long term continuous antiandrogen therapy is chosen as appropriate therapy — localized irradiation to the prostate does improve prostate-cancer specific survival and OS. Whether continuous antiandrogen therapy is necessary in these patients is not addressed by these data; however, substantial trials evidence demonstrates the merit of androgen combined-modality therapy in patients with high-risk, apparently localized prostate cancer. Unfortunately, there are not clear data with regard to the optimal duration of antiandrogen therapy in the multimodality management of localized disease.
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