In Prostate Cancer, ADT After RT Better Than Before RT

Pam Harrison

October 30, 2020

For patients with localized prostate cancer who undergo radiotherapy, giving androgen deprivation therapy (ADT) in the adjuvant setting leads to better oncologic outcomes than occur with up-front neoadjuvant ADT, which is how it is usually given.

This new finding comes from an analysis of individual patient data from two large randomized trials, and it could change a clinical practice that has been going on for a decade, if not longer, say experts.

In one of the two trials, ADT was initiated before radiotherapy and was continued during it (neoadjuvant); in the other, ADT was given after radiotherapy or was started during it but not before (adjuvant).

In both settings, the duration of ADT was similar.

"Thus, it's really a question as to whether you should start ADT months before radiation or whether you should start it when you start radiation and continue on afterwards," explained lead author Daniel Spratt, MD, an associate professor of radiation oncology at the University of Michigan, Ann Harbor, Michigan.

"The hypothesis of this study was that sequencing of ADT with radiotherapy independent of ADT duration will have a clinically meaningful impact on oncologic outcomes just as it does in other disease sites," he told Medscape Medical News.

"We found that progression-free survival, biochemical recurrence, distant metastases, and metastases-free survival were all significantly improved with adjuvant compared with neoadjuvant ADT sequenced with prostate-only radiation, and we believe this analysis currently serves as the highest level of evidence to support the importance of sequencing of ADT with radiotherapy," he concluded.

Spratt presented the new data at the virtual annual meeting of the American Society for Radiation Oncology (ASTRO).

This is a "startling" finding and one that challenges the way physicians have combined ADT and radiotherapy over the past decade or even longer, commented Alison Tree, MBBS, MD, consultant clinical oncologist, the Royal Marsden Hospital and the Institute of Cancer Research in London, the United Kingdom. She was not involved in the study and was approached for comment.

"In a large group of patients, all recruited to high-quality randomized trials and with long follow-up, starting ADT with radiotherapy significantly improved meaningful outcomes for patients, compared to starting ADT months before radiotherapy," she told Medscape Medical News in an email.

This benefit was achieved at no cost, Tree added. Side effect rates appear to be no different from those when starting ADT earlier.

This finding has the potential to make a big difference to many men receiving curative treatment for prostate cancer. Dr Alison Tree

"This finding has the potential to make a big difference to many men receiving curative treatment for prostate cancer," Tree underscored.

Lowers Testosterone

Explaining the rationale behind the study, Spratt, who is also chair of the genitourinary clinical research program at the University of Michigan's Rogel Cancer Center, noted that ADT systemically lowers testosterone to starve cancer cells. "If you have two different therapies, one being hormone therapy and the other radiation, it probably doesn't matter if you use them together or one before the other or one after the other, because each are just giving their independent effects if they are simply additive," he said.

However, if the effect of the two therapies is synergistic — which, for example, is how chemotherapy works in tandem with radiotherapy in other cancers — then sequencing should matter.

Spratt explained that when radiotherapy is given for patients with prostate cancer, it upregulates the androgen receptor, which is what testosterone binds to and which is the driver of prostate cancer.

"The androgen receptor controls a lot of the DNA repair genes that fix the radiation damage, so when you radiate prostate cancer cells, it upregulates the androgen receptor, and then that receptor tells it to repair that radiation damage," Spratt noted.

However, radiation damage can continue long after the radiotherapy itself has been completed.

"So by keeping the androgen receptor inhibited or suppressed by hormone therapy, you can suppress that DNA repair mechanism for months, and this is why I think adjuvant ADT is a very important component to kill prostate cancer cells," Spratt told Medscape Medical News.

Spratt added, however, that some men have very aggressive locally advanced tumors. For these men, hormone therapy can shrink the prostate, making treatment safer.

In this setting, neoadjuvant ADT may be intentionally given not for any oncologic benefit but to achieve cytoreduction of the tumor and, potentially, to alleviate symptoms if the tumor is pushing on the rectum or bladder.

This point was emphasized by Marc Garnick, MD, professor of medicine at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, who was approached for comment. The whole intent of giving neoadjuvant therapy for prostate cancer has been to shrink the tumor, allowing radiation oncologists to deliver appropriate doses of radiotherapy to a smaller gland, he explained.

"There were also some data to suggest that androgen deprivation actually enhanced the sensitivity of radiation therapy's anticancer activity," he said.

However, the authors of this new analysis are suggesting that there may be some independent effects of radiotherapy that could allow ADT given afterward to be even more effective than it would be in the neoadjuvant setting.

"The study certainly should serve as a basis for a formal randomized study to prospectively establish the superiority of this sequence," Garnick added. If proven to be the case, "this would be practice changing," he emphasized.

However, there will be patients for whom physicians might want to initiate ADT immediately, so each case would have to be individualized, he added.

Details of the Combined Analysis

For their study, Spratt and colleagues carried out the first combined individual patient analysis of two phase 3 randomized trials to determine the optimal timing of ADT with radiotherapy for patients with localized prostate cancer. In the neoadjuvant group, ADT was initiated a few months prior to starting radiotherapy, and it was continued during radiotherapy; in the adjuvant group, ADT was given after radiotherapy or was initiated during it.

Data from 1065 patients were analyzed. The neoadjuvant and the adjuvant groups had the same number of patients. The two cohorts were extremely well matched, Spratt commented: more than 50% of both groups had Gleason 7 disease; the majority had palpable disease (T2 or T3); and baseline prostate-specific antigen levels were greater than 10 ng/mL in the majority of patients.

The primary endpoint was progression-free survival (PFS); median follow-up was 14.9 years.

For all oncologic outcomes with the exception of prostate cancer–specific survival and overall survival, adjuvant ADT was statistically superior to neoadjuvant ADT, Spratt reported. There was a 25% relative improvement in PFS with adjuvant ADT compared with neoadjuvant ADT, which translated into a 7% absolute improvement at 15 years' follow-up.

"Biochemical recurrence was significantly lower with adjuvant ADT, with a 37% relative improvement over neoadjuvant ADT and a 10% absolute improvement again at 15 years," Spratt observed.

The cumulative incidence of distant metastases was also significantly lower with adjuvant ADT, with a 40% relative reduction compared with neoadjuvant ADT and a 6% absolute reduction at the same follow-up point.

Although the difference in prostate cancer–specific mortality between the adjuvant and neoadjuvant ADT groups did not reach statistical significance, it was numerically lower in the adjuvant group, at a 29% relative reduction at 15 years' follow-up, Spratt noted. The difference in overall survival between the adjuvant and the neoadjuvant ADT groups was also not significant.

"These improvements were accomplished without an increase in late grade 3 to 5 genitourinary and gastrointestinal toxicity," he observed, "and the cumulative incidence of late-grade toxicity was low regardless of ADT sequencing."

Sprat concluded: "We demonstrate for the first time that sequencing of ADT with radiotherapy significantly impacts long-term oncologic outcomes in localized prostate cancer, favoring an adjuvant rather than neoadjuvant-based approach, without increasing late toxicity."

Spratt has disclosed no relevant financial relationships. Garnick is editor-in-chief of Harvard Prostate Knowledge and Harvard Medical School's Annual Report on Prostate Diseases.

American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting: Abstract 32, presented October 24, 2020.

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