New Data on RT in Prostate Cancer Are 'Practice Changing'

Alexander M. Castellino, PhD

October 22, 2018

UPDATED WITH COMMENTARY // MUNICH — Radiotherapy to the prostate on top of standard hormonal therapy significantly improved overall survival (OS) for men with newly diagnosed metastatic prostate cancer (mPCa) with low metastatic burden, according to new data from the STAMPEDE trial.

However, it was just this subgroup of patients who had the benefit; the OS benefit did not extend to the total unselected population of men with newly diagnosed mPCa.

The results come from the multi-arm STAMPEDE study; specifically, from a phase 3 comparison to evaluate whether or not radiotherapy improved OS in men with newly diagnosed mPCa.

They were presented here at the European Society of Medical Oncology 2018 annual meeting and simultaneously published in The Lancet.

"Prostate radiation therapy should be the standard of care for men with low metastatic burden," commented lead investigator Christopher C. Parker, MD, of the Royal Marsden NHS Foundation Trust, London, UK.

Christopher C. Parker, MD

"Until now, it was thought that there was no point in treating the prostate itself if the cancer had already spread because it would be like shutting the stable door after the horse has bolted," Parker said at the press conference.

"However, this study proves the benefit of prostate radiotherapy for these men. Unlike many new drugs for cancer, radiotherapy is a simple, relatively cheap treatment that is readily available in most parts of the world," he added.

Commenting on the findings for ESMO, Karim Fizazi, MD, PhD, from the Gustave Roussy Institute, University of Paris Sud, France, said: "For the first time, this study provides evidence that treating the local primary tumor is associated with improvement in OS in men with mPCa and minimal disseminated disease."

Study Details

Standard treatment for men newly diagnosed with mPCa is currently drug treatment alone, Parker explained in an ESMO press release. "Although outcomes have improved, men still typically die from mPCa within around 5 years, so there is a need for more effective treatment. We wanted to know if radiotherapy to the prostate might not only improve local control but also slow progression of metastatic disease," he said.

The rationale for the study was provided by animal models in which local treatment of the primary tumor not only inhibited the initiation of distant metastases, but also the progression of existing metastases, Parker pointed out.

The STAMPEDE investigators randomized 2061 men with newly diagnosed mPCa to receive either standard-of-care androgen deprivation therapy (ADT) or ADT and radiotherapy. After docetaxel was approved for use in this patient population in 2015, its use was left to the discretion of the investigator.

Men received lifelong ADT; docetaxel was provided at a schedule of six 3-weekly cycles of 75 mg/m2.  

External beam radiotherapy (EBRT) to the prostate was given on a weekly (36 Gy in six weekly fractions of 6 Gy) or daily (55 Gy in 20 daily fractions of 2.75 Gy over 4 weeks) schedule, which was decided prior to randomization.

All endpoints were analyzed for the overall population and for the subpopulation of men with high and low metastatic burden.

Results

Baseline characteristics were well balanced for patient and disease characteristics. Men were 68 years at diagnoses; prostate specific antigen was 98 ng/mL; 42.5% of men had low metastatic burden, and 57.5% had high metastatic burden. Bone was the site of metastases in 89% of men; 18% of men had used docetaxel before radiotherapy.

The primary endpoint of OS was similar for patients in the control group and those receiving radiotherapy (hazard ratio [HR], 0.92; P = .266). At 3 years, OS was 65% for patients receiving radiotherapy and 62% for men in the control arm. When OS was analyzed based on the EBRT schedule, OS remained not significant. "There was no evidence that effect size differed with the radiotherapy schedule. If there was a benefit, it was in men with low metastatic burden," Parker said.

Significant improvement in OS was seen in the subgroup of men with low burden metastatic disease (HR, 0.68; P = .007); 3-year OS rates were 73% for the control vs 81% for the radiotherapy group.

For patients with a high metastatic burden, OS was not significant, with an HR of 1.03. Three-year OS rates were 54% for the control vs 53% for the radiotherapy group.

Parker provided a convincing rationale as to why the positive OS data in men with low metastatic burden was credible. "Our subgroup finding meets all the criteria proposed to assess credibility of subgroup effects," he said. Among these he pointed out that low metastatic burden status was determined before randomization and before bone scans were taken; the effect was hypothesized a priori; the subgroup effect was independent of other variables tested; the subgroup effect was large; the subgroup outcomes were consistent with other outcome measures in STAMPEDE (eg, failure-free survival).

In addition, these data mirrored data from the HORRAD study, which demonstrated an HR of 0.68 for patients with less than five bone metastases (vs an HR of 1.06 for men with five or more bone metastases).    

"It also seems plausible that the effect of local radiotherapy would be diminished in patients with a greater burden of metastatic disease," Parker and colleagues write in their published report. "There is, therefore, good reason to accept that prostate radiotherapy improves survival of men with a low metastatic burden and that it should now be a standard treatment," they add.

Radiotherapy was well tolerated. "There was a small increase in risk of bladder and bowel side effects but these were modest. The side effects are certainly outweighed by the survival benefit," Parker said.

Fizazi suggested: "For men with newly diagnosed oligometastatic prostate cancer, it is quite likely that these data are practice changing."

Questions Arising

When asked whether prostate surgery would have the same effects as radiotherapy to the prostate, Parker indicated that patients in this study had not had surgery. "It is not possible to answer this question," he said.

However, discussant for the study Robert Bristow, MD, PhD, director of the Manchester Cancer Research Centre, UK, noted that retrospective reviews point to an OS benefit with systemic therapy and radical prostatectomy. He noted that surgery is being tested in randomized clinical trials (g-RAMMP and TROMBONE). "If positive, these trials would start to inform a trial between surgery and radiotherapy in terms of efficacy and quality of life," Bristow said.

Parker suggested that the study results are also relevant to men with pelvic node positive but nonmetastatic disease (N1M0) where addition of radiotherapy to drug treatment could be curative. Bristow noted that no trial has looked at the role of radiotherapy in N1M0 disease. "However, retrospective studies support irradiation for N+ disease," he said.

Looking to the future, Fizazi said: "For men with higher burden of disease, more data are needed regarding whether upfront local treatment improves or prevents local symptoms, which by itself, may justify its use in the absence of an OS benefit."

Fizazi noted that although the study was large, only 18% of the patients had received early docetaxel and none had received early abiraterone, although these treatments are now part of standard treatment in fit men.

Bristow noted that future trials will answer questions regarding roles for different radiotherapy volumes, surgery vs radiotherapy, modern imaging, systemic therapies (including immunotherapy), and use of ablative therapies to metastases.

Patient Perspective

A patient perspective was provided in a Royal Marsden press statement. Kevin Webber, age 53, received radiotherapy to the prostate as part of his treatment for advanced prostate cancer at the institute, although he was not involved in the trial. He said: "I discovered I had prostate cancer in November 2014 and was given a prognosis of as little as 2 years. My tumor had spread to lymph glands in my abdomen and chest, so I didn't think radiotherapy was an option for me until Dr Chris Parker raised the possibility of it."

"Now, nearly 4 years on from my diagnosis, I'm still incurable — but have been and currently remain fit enough to have just completed my sixth multiday ultra-marathon of 2018. Groundbreaking studies like STAMPEDE give patients hope, and that's priceless when you have advanced cancer," he said in the press statement.

Hypothesis-Generating Data

Reacting to the new STAMPEDE results presented at the ESMO meeting, Anthony D'Amico, MD, PhD, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, Massachusetts, provided Medscape Medical News with his comments by email.

He said that these new data from STAMPEDE, as well as similar data from HORRAD, taken together "raise the hypothesis that that definitive local therapy (radiotherapy, and perhaps radical prostatectomy) in men with a low burden of metastatic prostate cancer (that is, three or less bone metastases and no visceral metastasis) prolongs overall survival."

"Therefore, one could consider such an approach in a motivated otherwise healthy patient who presents with low-burden M1 prostate cancer after a discussion detailing that there may be a prolongation in survival but this remains to be proven," he added.

In STAMPEDE, the results on radiation are from a prespecified subgroup analysis in men by metastatic disease burden.

"However, men were not stratified by metastatic disease burden prior to randomization, so the results within these subgroups are considered hypothesis generating," he cautioned.

European Society for Medical Oncology (ESMO) 2018 Congress. Presented October 21, 2018. Abstract LBA5.

Lancet. Published online October 21, 2018. Full text

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