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Optimum Timing of Chemotherapy for Metastatic Prostate Cancer: Early or Wait?

Carlson, Robert H.

doi: 10.1097/




CHICAGO—Patients with hormone-naive metastatic prostate cancer can benefit from chemo-hormonal therapy, and today the standard combination would be androgen deprivation and docetaxel. But when should the chemotherapy start—immediately or at progression? That question was debated here at American Society of Clinical Oncology by two eminent urological oncologists.

Give chemotherapy early, said Maha Hussain, MD, Professor of Medicine and Urology and Associate Director for Clinical Research at the University of Michigan Comprehensive Cancer Center.

Wait until progression, said Howard I. Scher, MD, Chief of the Genitourinary Oncology Service and Chair in Urologic Oncology at Memorial Sloan Kettering Cancer Center.

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Maha Hussain: Kill Cancer Cells Early



“Kill cancer cells, and kill all of them early!” was the theme of Maha Hussain's talk, and the most effective way to do that, she said, is with combination chemo-hormonal therapy.

The concept of treating advanced prostate cancer with early chemotherapy is not new: “The rationale when I was a fellow was the same as now, that androgen deprivation is not good enough because of the heterogeneity of prostate cancer.”

Hussain cited a recent report suggesting that sequential use of current androgen-receptor targeted agents is not associated with optimal efficacy (Azad et al: European Urology 2015;3:441-447). “Targeting the disease early, at the micro level, has the greatest impact on survival,” she said.

Hussain said that in metastatic hormone-naive prostate cancer, docetaxel plus androgen-deprivation therapy significantly improves overall survival compared with androgen deprivation alone, as seen in the CHAARTED (2014 ASCO Annual Meeting Abstract LBA2) and STAMPEDE (2015 ASCO Annual Meeting Abstract 5001) trials.

“CHAARTED showed that patients with high-volume metastatic disease had an unprecedented 17-month improvement in overall survival,” she said, although longer follow-up is required for patients with low-volume metastatic disease.

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5 Requirements for Success

  • Hussain listed five requirements for success of systemic disease therapy in any setting:
  • Unmet need or a justification to treat;
  • Biological rationale for a multi-targeted strategy;
  • Effective and feasible therapy safe to administer;
  • Appropriate patient selection; and
  • An adequately powered trial.

For every point there is a “yes” for the data supporting early chemotherapy, she said.

  • Unmet need: The need is obvious—metastatic prostate cancer is deadly. Data from SWOG 9346 (JCO 2006;24:3984-3990) and other trials show that even in the PSA era, this is a deadly disease with an overall survival of four years.
  • Biological rationale for a multi-targeted strategy: Hormonal treatment does not address all the elements of metastatic disease, she said. There are multiple mechanisms for progression such as clonal selection and molecular adaptation, and much of that is independent of the androgen receptor. “And there certainly is data suggesting that in addition to blocking cell division, docetaxel will impair androgen receptor signaling—hence combining the two major targets makes a very strong rationale.”
  • Effective and feasible systemic therapy: “Absolutely, there is unequivocal improvement in overall survival.”
  • Appropriate patient selection: “We in this field have lagged behind others in regard to clinical trials using biomarker pre-selections, but I would say we do have biomarkers—namely the distribution of the disease, the magnitude of impact,” Hussain said. “Disease extent has clearly been shown to be a powerful prognostic factor for overall survival.”
  • Adequate sample size: To illustrate this point, Hussain again cited the CHAARTED randomized Phase III trial of 793 patients, which she said is now in press in the New England Journal of Medicine. That trial compared chemo-hormonal therapy with androgen ablation for extensive disease, with 87 percent of patients able to receive all six cycles of treatment, and 74 percent of patients not requiring a dose modification. “Here's the bottom line [to CHAARTED]—the most amazing median overall survival curve you have ever seen in the setting of metastatic prostate cancer—57.6 months for chemo-hormonal therapy versus 44 months for androgen-deprivation alone,” she said. “And for high-volume disease, overall survival was 49.2 months versus 32.2 months, a 17-month improvement!”
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GETUG-AFU 15 Differs

After reviewing CHAARTED Hussain addressed the GET-AFU 15 trial (Lancet Oncology 2013; 2:149-158), which appeared to have different results from CHAARTED (Gravis et al: 2015 ASCO GU Symposium Abstract 140). The GETUG-AFU 15 Phase III trial with 385 patients compared androgen-deprivation therapy plus docetaxel with androgen deprivation alone for patients with hormone-naive metastatic prostate cancer. That trial showed a nonsignificant longer median overall survival for patients receiving chemo-hormonal therapy—60.9 months versus 46.5 months for hormonal therapy alone.

The results of GEFUG-AFU 15 were not inconsistent with those of CHAARTED, she said, but there were important differences between the two—namely the size of the trial (514 for CHAARTED vs. 183 for GEFUG-AFU 15), and volume of disease.

“Fewer than half of the patients in GEFUG-AFU 15 had high-volume disease compared with two-thirds of patients in CHAARTED,” she said. The overall lower volume of disease was also reflected in the median PSA of CHAARTED—approximately 20 ng/mL, compared with more than 50 ng/mL in CHAARTED.

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‘Smart Cancer’

“Metastatic prostate cancer is a complex, ‘smart cancer’ with marked inter- and intra-patient heterogeneity,” Hussain said. “Androgen receptor signaling is important, but it's not the whole story.”

The limitation of androgen deprivation, coupled with the established biologic heterogeneity of prostate cancer and its adaptation capability, provide the rationale for a preemptive multi-targeted strategy aimed at a cytotoxic impact.

“We stand at a crossroads,” Hussain concluded. “Do we alter the standards of care, or do we bury our heads in the sand?”

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Howard Scher: Wait for It



“Clearly [from recent clinical trials] there are patients who benefit from the combination of androgen-deprivation therapy and docetaxel as initial therapy,” Howard Scher said. What the trials have not addressed, though, is whether deferring chemotherapy until the earliest signs of progression, when PSA is beginning to rise, will not provide similar outcomes.”

There is Level 1 evidence that chemo-hormonal therapy can prolong survival, but it is important to consider this in context of “what we know, when we know about it, and how do we actually use that information in practice.”

The final clinical interpretation of CHAARTED was unequivocally positive, Scher said, and in 2014, the National Comprehensive Cancer Network guidelines quickly added the option of that six cycles of docetaxel in addition to androgen-deprivation therapy as representing an appropriate option.

“But it was notable that this was before a full dataset was available, before the data were subject to critical peer review or published,” he said.

Clinical trial results that have been published only in abstract forms and presented at scientific meetings should be interpreted cautiously, Scher cautioned, and the outcomes observed in a population of men who met protocol-specific criteria and deemed “fit for chemotherapy” cannot be extrapolated to all men at the same point in the disease.

Early adoption has risks, Scher said, cautioning physicians on the use of approaches where the true risk-benefit ratio cannot be explained.

A range of systemic options are now available for men with metastatic prostate cancer, “and I would argue that the door is still open to ask questions about what potentially are new standards of care. But at present we do not know the optimal timing or sequence to use them to maximize benefit for an individual patient.”

“Delaying progression may be beneficial, but it does not assure a survival benefit.”

Turning to the key studies in this debate, Scher also compared GETUG-APU 15 with CHAARTED: “The top-line results were no survival benefit in GETUG-APU 15 and a dramatic, unprecedented improvement in CHAARTED.”

But some important high-level differences could explain those contradictory outcomes, he said: GETUG-APU 15 had fewer enrolled patients—385 versus 790 for CHAARTED; median follow-up was 83 months for GETUG-APU 15 versus 29 months for CHAARTED; fewer men had high-volume disease in GETUG-APU 15 versus CHAARTED—48 versus 65 percent; and GETUG-APU 15 patients received six cycles of docetaxel therapy versus nine in CHAARTED.

Allowing for these differences, there was only a small survival difference between the studies, Scher said.

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Not ‘Real World’

Regardless of trial results, protocol-eligible patients do not represent “the real world,” Scher said. Eligibility for protocols is optimal for favorable outcome, and all patients in these trials were fit for chemotherapy and likely had fewer comorbidities.

Outcomes with “standard” therapy are often inferior “off study” as opposed to “on protocol,” Scher said, citing a study by Templeton and Tannock et al (Ann Oncol 2013;12:2972-2977). “Timing may be everything,” Scher said, referring to starting chemotherapy “early” versus “late.”

Some trials consider “late chemotherapy” to start when castrate-resistant disease starts, others when there is radiographic evidence, and still others consider late to be when symptoms develop. But that means, unfortunately, that many men who might benefit from chemotherapy never receive it, he said.

“There is no question that it is tempting to recommend docetaxel plus ADT to all patients with non-castration metastatic disease, particularly those with high-volume tumors, but the results of GETUG-AFU 15 cannot be ignored,” Scher said.

Docetaxel is commonly used and its adverse events well known, but it can be toxic and lethal, and in the absence of the details of outcomes, the risk-benefit for individual cannot be assessed.

“We all know STAMPEDE has arrived, but it is very important to look very carefully at the data and make sure we are not jumping to conclusions and potentially doing harm by overtreating patients,” Scher concluded.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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