Docetaxel for Prostate Cancer: ‘Win-Win-Win’


Adding the chemotherapy docetaxel to standard hormone therapy for both metastatic and nonmetastatic prostate cancer is a win-win-win because it improves patients’ overall quality of life (QoL), reduces the need for subsequent therapy, and is cost-effective, according to a new modeling study from the investigators of a major clinical trial.

That trial, known as STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy), helped establish that docetaxel was an effective option in the treatment of metastatic prostate cancer (Lancet. 2016;387:1163-1177). The study showed a 10-month overall survival benefit when the drug was added to androgen deprivation therapy (ADT) for hormone-sensitive metastatic prostate cancer compared with ADT alone.

However, use of docetaxel in nonmetastatic disease has been considered controversial  because the difference in survival was not as pronounced in this earlier stage of disease as it was in metastatic disease and did not reach statistical significance, as reported at the time by Medscape Medical News.

Now, the lead author of STAMPEDE, Nicholas D. James, MD, PhD, professor of clinical oncology, University of Birmingham, United Kingdom, is championing the idea.

“Results suggest use of docetaxel in selected nonmetastatic patients should be considered,” he said in a presscast ahead of the Genitourinary Cancers Symposium (GUCS) 2018, which will be held later this week in San Francisco.

The triple benefit (QoL, less need for more therapy, cost-effectiveness) seen in nonmetastatic disease is “somewhat surprising and may cause clinicians to rethink how and when they use docetaxel to treat prostate cancer,” he said.

Dr James will be presenting results from the new modeling study, which  calculated lifetime predictions of costs, changes in predicted survival duration, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. The researchers used data on both men with metastatic (M1) and nonmetastatic (M0) disease, as the trial included both populations.

Health outcomes and costs in the UK National Health Service were modeled by using EuroQol (EQ-5D), which is a standardized self-reporting tool, and resource-use data collected within the STAMPEDE trial. In the trial, standard of care was ADT for at least 2 years and, in some patients, radiotherapy. Docetaxel (75 mg/m2) was administered alongside standard of care for six 3-weekly cycles with prednisolone 10 mg daily.

The team reported that docetaxel was estimated to extend predicted survival by an average of 0.89 years for M1 patients and 0.78 years for M0 patients, compared with patients receiving standard of care.

Docetaxel was also estimated to extend QALYs by 0.51 years in M1 patients and 0.39 years in M0 patients — and the findings for this measure had a “high degree of certainty,” Dr James commented. QALY gains in M0 patients were driven by the “beneficial effect of delayed and reduced relapse,” the authors said.

Compared with standard of care, docetaxel was cost-effective in both M1 patients and M0 patients. A sensitivity analysis indicated a “very high probability” (>99%) that docetaxel is cost-effective in both M0 and M1 patients, the authors also stated. Docetaxel remained cost-effective in M0 patients because of reductions and delays in relapse; this held true even when no survival advantage was assumed.

How Does This Compare to Abiraterone?

The new data prompted Sumanta K. Pal, MD, an American Society of Clinical Oncology (ASCO) expert and urologic oncologist at City of Hope, Duarte, California, and moderator of the GUCS presscast, to think about another drug used in this setting, abiraterone (Zytiga, Janssen).

“I will be interesting to assess these results [ie cost and QoL for docetaxel] against recent data for abiraterone, an oral hormonal therapy for prostate cancer, which has similar benefit in the same settings in prostate cancer,” he told reporters.

“Abiraterone may have the benefit of improved tolerability over a short course vs chemotherapy but does require a much more extensive duration of use and further mandates concomitant intake of prednisone, a steroid,” Dr Pal said.

Understanding the cost and quality of life associated with abiraterone may help in selecting either it or docetaxel for these patients with prostate cancer, he summarized.

Press materials from ASCO further pointed out that docetaxel is much less expensive: For the average patient with prostate cancer in the United Kingdom, a course of docetaxel costs £5000 (approximately $6000) per year, compared with £24,000 ($28,800) for abiraterone.

Seven-Month Prostate-Specific Antigen Is Prognostic in Metastatic Hormone Sensitive Prostate Cancer Treated With Androgen Deprivation With Or Without Docetaxel.


Abstract

Purpose We evaluated the relationship between prostate-specific antigen (PSA) and overall survival in the context of a prospectively randomized clinical trial comparing androgen-deprivation therapy (ADT) plus docetaxel with ADT alone for initial metastatic hormone-sensitive prostate cancer. Methods We performed a landmark survival analysis at 7 months using the E3805 Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) database ( ClinicalTrials.gov identifier: NCT00309985). Inclusion required at least 7 months of follow-up and PSA levels at 7 months from ADT initiation. We used the prognostic classifiers identified in a previously reported trial (Southwest Oncology Group 9346) of PSA ≤ 0.2, > 0.2 to 4, and > 4 ng/dL. Results Seven hundred nineteen of 790 patients were eligible for this subanalysis; 358 were treated with ADT plus docetaxel, and 361 were treated with ADT alone. Median follow-up time was 23.1 months. On multivariable analysis, achieving a 7-month PSA ≤ 0.2 ng/dL was more likely with docetaxel, low-volume disease, prior local therapy, and lower baseline PSAs (all P ≤ .01). Across all patients, median overall survival was significantly longer if 7-month PSA reached ≤ 0.2 ng/dL compared with > 4 ng/dL (median survival, 60.4 v 22.2 months, respectively; P < .001). On multivariable analysis, 7-month PSA ≤ 0.2 and low volume disease were prognostic of longer overall survival (all P < 0.01). The addition of docetaxel increased the likelihood of achieving a PSA ≤ 0.2 ng/dL at 7 months (45.3% v 28.8% of patients on ADT alone). Patients on ADT alone who achieved a 7-month PSA ≤ 0.2 ng/dL had the best survival and were more likely to have low-volume disease (56.7%). Conclusion PSA ≤ 0.2 ng/dL at 7 months is prognostic for longer overall survival with ADT for metastatic hormone-sensitive prostate cancer irrespective of docetaxel administration. Adding docetaxel increased the likelihood of a lower PSA and improved survival.

Adding therapeutic vaccine to docetaxel ups PFS in metastatic breast cancer


Adding the investigational therapeutic cancer vaccine PANVAC to docetaxel prolongs progression-free survival (PFS) in patients with metastatic breast cancer, a phase II study finds. [JAMA Oncol 2015, doi:10.1001/jamaoncol.2015.2736]

“Previous vaccine monotherapy trials have often failed to demonstrate improvements in short-term endpoints, such as PFS, despite improvements in long-term outcomes, such as overall survival. This may be explained by the lag between initial vaccination and eventual slowing of tumour growth rate,” wrote investigators of the study. “If this hypothesis is correct, then combining therapeutic cancer vaccines with standard-of-care agents may provide adequate time for the vaccines to take effect, resulting in improved PFS compared with the standard agents alone.”

In the study, 48 patients with metastatic breast cancer were randomized to receive docetaxel alone or in combination with PANVAC. Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoint of PFS, although not statistically significant, favoured the combination arm (median, 7.9 months vs 3.9 months in the docetaxel-alone arm; hazard ratio, 0.65; p=0.09). “The statistical insignificance was likely owing to the small number of patients enrolled in this study,” the investigators noted.

Partial response was achieved in 16 percent of patients in the combination arm and 13 percent of patients in the docetaxel-alone arm.

The overall safety profile was comparable between the two arms, with the exception of significantly higher rates of injection site reactions (64 vs 0 percent; p<0.001) and oedema (44 vs 13 percent; p=0.02) in patients receiving PANVAC plus docetaxel. The investigators added, however, that the higher incidence of oedema observed in the combination arm was primarily due to the longer exposure to docetaxel as a result of prolonged PFS.

“We demonstrated that PANVAC can be safely combined with docetaxel to benefit patients with metastatic breast cancer,” they concluded. “These findings provide both a rationale and statistical assumptions for a larger definitive randomized study in a more uniform patient population.”

Patients who received PANVAC in this study were first given the priming vaccine PANVAC-V, followed by the monthly boosting vaccine PANVAC-F. With every vaccination, they also received an injection of granulocyte-macrophage colony-stimulating factor to boost the immune system.

Drug for Advanced Prostate Cancer Approved.


The Food and Drug Administration (FDA) has approved enzalutamide (Xtandi) to treat men with advanced prostate cancer that has spread or recurred after medical or surgical therapy to minimize testosterone, which fuels tumor growth. The drug was approved for use in prostate cancer patients previously treated with docetaxel.

The safety and effectiveness of enzalutamide—previously called MDV3100—was evaluated in a study of 1,199 patients with metastatic castration-resistant prostate cancer who had received prior treatment with docetaxel. The median overall survival for patients who received enzalutamide was 18.4 months, compared with 13.6 months for those who received a placebo.

The most common side effects were fatigue, back pain, diarrhea, joint pain, hot flush, tissue swelling, musculoskeletal pain, respiratory infections, dizziness, spinal cord compression, blood in urine, tingling sensation, anxiety, and high blood pressure.

Seizures occurred in about 1 percent of those receiving enzalutamide. Study participants who had a seizure stopped enzalutamide therapy. The clinical study excluded men who had a history of seizure or several other brain conditions or who were taking medications that may cause seizures. The safety of enzalutamide in patients with these conditions is unknown.

Enzalutamide was reviewed under the FDA’s priority review program, which allows an expedited 6-month review for drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists.

Source: NCI