Timing of Chemotherapy, Ra 223 in Advanced Prostate Cancer

Timing of Chemotherapy, Ra 223 in Advanced Prostate Cancer

Dr. Maha Hussain

In the last 2 years, treatment options for men with metastatic prostate cancer (mPC) have expanded substantially. That’s why it is appropriate to focus on when to administer chemotherapy to these men and how radium 223 (Ra 223), a drug that was approved based on bone metastases, fits into the treatment landscape. These issues were discussed during the Education Session “Debate on Chemotherapy and Radium 223 for the Optimal Treatment of Advanced Prostate Cancer,” held Friday, May 29.

Why Chemotherapy Should Be Given Early

Maha Hussain, MD, FACP, FASCO, of University of Michigan Comprehensive Cancer Center, argued that chemotherapy should be given early for men with mPC, especially for those with high-volume disease. She supported her argument with data from randomized clinical trials on early delivery of chemotherapy plus androgen deprivation therapy (ADT) for men with high-volume disease.

In appropriate patients, there is an unmet need for better systemic therapy, a biologic rationale for multitargeted therapy (chemotherapy plus ADT), and data from randomized studies that show improved survival, Dr. Hussain said.

Data from several SWOG/Intergroup trials and from The University of Texas MD Anderson Cancer Center showed that disease extent is a powerful prognostic factor for overall survival (OS). Dr. Hussain highlighted data from the CHAARTED study, presented during the 2014 ASCO Plenary Session and now in press in New England Journal of Medicine. In CHAARTED, men with advanced PC were randomly assigned to receive a standard dose of docetaxel with ADT for a maximum of six cycles (397 patients) or ADT therapy alone (393 patients). The protocol was initially restricted to recruiting men with high-volume disease.

Of 397 men in the chemotherapy plus ADT arm, 87.5% received all six cycles of therapy. Median OS, the primary endpoint, was significantly higher for men who received chemotherapy plus ADT (57.6 vs. 44.0 months for ADT alone; hazard ratio [HR] 0.61, 95% CI [0.47, 0.80]; p = 0.0003).

“Significantly, in patients with high-volume disease, there was a 17-month improvement in median OS from 32.2 months to 49.2 months,” Dr. Hussain said.

In addition to the OS benefit, other important endpoints of benefit—including rate of undetectable prostate-specific antigen (PSA), median time to castration resistance, and median time to clinical progression—were all significantly longer with docetaxel plus ADT compared to ADT alone. Dr. Hussain also presented long-term data from GETUG-AFU 15 (median follow-up: 82.9 months), which showed nonsignificant longer median OS for patients who received chemotherapy with ADT (60.9 vs. 46.5 months for ADT alone; HR 0.9, 95% CI [0.7, 1.2]; p = 0.44). These data may appear to be inconsistent with CHAARTED, Dr. Hussain said. But she also pointed out that GETUG-AFU 15 was a smaller trial than CHAARTED (183 vs. 514 patients, respectively).

Dr. Hussain also highlighted data from the STAMPEDE trial that will be presented at the 2015 ASCO Annual Meeting showing higher OS for patients receiving docetaxel plus ADT, including those with metastatic disease. Finally, she broadly contrasted the magnitude of the survival improvement by early use of docetaxel in the setting of hormone-sensitive mPC to treatment burdens, including lower survival benefit and higher cost of therapy.

Why Chemotherapy Should Be Given Late

Dr. Howard Scher

Taking an opposing view, Howard I. Scher, MD, of Memorial Sloan Kettering Cancer Center, indicated that prior to the advent of CHAARTED, use of chemotherapy in the first-line setting of castration-resistant PC (CRPC) was not recommended for the optimum treatment of patients. “It is important to discuss this opinion in the context of what we know, when we know it, and how we put it into clinical practice,” he said.

Although the clinical interpretation of CHAARTED was positive, and six cycles of docetaxel plus ADT was recommended by the National Comprehensive Cancer Network even before the CHAARTED data were peer reviewed, “the outcomes observed in a population of men who met protocol-specific criteria and were deemed ‘fit for chemotherapy’ cannot be extrapolated to all men at the same point in the disease,” Dr. Scher said. He proceeded to compare GETUG-AFU 15 and CHAARTED to discuss disparity in data, generalization of clinical trial data, early versus late treatment, and timing of chemotherapy.

For Dr. Scher, the disparities between GETUG-AFU 15 and CHAARTED were explained on the basis of more docetaxel used in GETUG-AFU 15 (nine vs. six cycles) and the lower number of patients with high-volume disease (48% vs. 65%). Indeed, he showed that applying the CHAARTED disease metrics to GETUG-AFU 15 did not change the outcomes and that the absolute survival difference was small between the two studies.

With respect to “early” versus “late” chemotherapy, Dr. Scher said that there are no standard definitions—a maximum of 4 months may be deemed a practical approach for defining “early,” and “late” may be defined from PSA progression, radiographic progression, or clinical progression.

Finally, Dr. Scher explained that trials relative to the approval of life-prolonging therapies are quite revealing. GETUG-AFU 15 was completed at a time when therapies such as abiraterone, Ra 223, enzalutamide, and cabazitaxel were not available—these therapies were approved a few years after CHAARTED was initiated. “The docetaxel plus ADT arm in CHAARTED received 25% more courses of a life-prolonging therapy and 50% more taxane than the corresponding arm in GETUG-AFU 15,” he said.

Although it is tempting to recommend docetaxel plus ADT to all patients with non-castration metastatic disease, GETUG-AFU 15 cannot be ignored, Dr. Scher suggested.

“The effect of post-protocol therapy on outcomes is real, and the question of the optimal time to use chemotherapy in light of the other options now available remains open,” he concluded.

Ra 223: Defining Patient Selection, Timing, and Duration

Tanya Dorff, MD, of Keck School of Medicine of USC and Norris Comprehensive Cancer Center, provided insights into which patients with mCRPC may best benefit from Ra 223.

Ra 223 was approved for treating mCRPC in men experiencing pain from bony metastatic diseases and no visceral involvement. Yet now that there are several therapeutic options available for treating this patient population, new questions, such as optimum patient selection and timing of treatment with Ra 223, remain unanswered for clinicians.

Dr. Dorff summarized data from the ALSYMPCA trial—the pivotal study leading to the approval of Ra 223. In ALSYMPCA, men experiencing pain related to bone metastases were randomly assigned to receive six injections of Ra 223 (621 patients) or placebo (307 patients).

Eighty-five percent of the population had more than six bone lesions, 54% were using opioids for pain relief, 41% had prior bisphosphonate therapy, and 58% of patients had been previously treated with docetaxel.

Median OS was significantly higher for patients receiving Ra 223 (14.9 vs. 11.3 months for placebo; p = 0.002). Time to symptomatic skeletal events was also significantly prolonged for patients who received Ra 223 (12.2 vs. 6.7 months; HR 0.64, 95% CI [0.52, 0.78]).

In discussing patient selection for Ra 223, Dr. Dorff presented data from the subset analyses, which showed that all subgroups benefited from Ra 223. For instance, although patients with lower serum alkaline phosphatase (< 220 U/L) at baseline had less significant OS benefit (HR 0.82, 95% Cl [0.64 to 1.07]), this group did have a statistically significant delay in time to symptomatic skeletal related events (16.5 vs. 10.2 months; HR 0.64, 95% CI [0.48, 0.86]).

“There is also a sense from the subgroup analyses that higher volume of disease benefitted more, as the moderately sized subgroup with less than six metastases did not maintain a significant difference in survival,” Dr. Dorff said.

She provided conceptual arguments for early versus later use of Ra 223. An argument for early use is the clinical importance of bone control. “The longer we can keep our patients free of pain and fractures and the less cord compression we see, the better,” Dr. Dorff said.

Based on the Expanded Access Protocol, as well as experiences at the Cleveland Clinic and Tulane University, Dr. Dorff indicated that Ra 223 may be used safely with abiraterone and enzalutamide.

Although prior use of abiraterone or enzalutamide is associated with men not completing the entire course of six doses, it is not known whether this impinges on lower efficacy. In this regard, she indicated that it is currently unknown whether all six doses of Ra 223 are required for optimum efficacy.

For Dr. Dorff, arguments against early use include the limited information on whether Ra 223 will affect future chemotherapy dosing and the need for longer-term follow-up to illuminate whether there is a risk of secondary malignancy.

Should Ra 223 be used before doce-taxel or after? Dr. Dorff noted that available data suggest Ra 223 can safely be used either before or after docetaxel. Whether higher doses or an extended dosing schedule will be associated with higher efficacy will be addressed in protocol NCT02023697.

The discussion that followed raised questions of appropriate sequencing of therapies such as Ra 223 and the combination of chemotherapy and ADT. In light of the presentations, it was suggested that such a question cannot be answered outside of a clinical trial setting, and clinical practice would dictate individualizing therapy based on patient characteristics.  

Watch the session, visit the ASCO Virtual Meeting website.