PCa Commentary #108: Adjuvant Deprivation Therapy Adjuvant To Radiotherapy: New Mechanistic Insights with Clinical Implications

A reasonable goal — especially from a patient’s point of view, in the use of androgen deprivation therapy (ADT) is capturing the benefits of androgen deprivation while reducing its well-recognized toxicity. This might be accomplished by reducing the duration of exposure or selecting and treating only those patients who will benefit.

Suggested regimens of ADT have varied widely, but even at this time the optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. The literature is replete with an extensive variety of schemas for combing ADT with radiotherapy. The duration of treatments prior to RT have ranged from 6 months to none at all. Therapy during and after RT ranged from of 4, 6, 18, 24,  36 months and 5 years — even for life. The focus has been on intermediate-risk (especially “unfavorable” intermediate-risk) and high-risk prostate cancer. These different regimens have for the most part been derived empirically in an attempt to build upon the best results of prior protocols. The current NCCN recommendation for adjuvant therapy for high-risk cancer is 2 – 3 years.

The Addition of ADT to Radiotherapy Improves Outcome — But Why?

A uniform finding throughout these various efforts is the firm observation that adjuvant androgen deprivation during and after radiation yields better outcomes as compared to no ADT. As summarized by Bartek et al. (Cancer Discovery, Nov 2013):

“In numerous clinical trials, such combined treatment showed improved disease-free and overall patient survival, for both high- and intermediate-risk prostate cancer when compared with radiotherapy alone. Although the clinical benefits of combining radiotherapy with androgen deprivation seem indisputable, this contrasts sharply with our lack of validated mechanistic understanding of the cellular and molecular basis for such synergistic therapeutic effects.”

Recent studies have provided deeper “mechanistic understanding” of both the counterproductive cellular response to radiation and the ameliorating effect of androgen deprivation.  Based on these observations (and likely more to come) the use and duration of ADT in association with radiation therapy in the future may be guided by a biologic rationale.

ADT enhances prostate cancer’s sensitivity to radiation therapy — Three studies:

Radiation damages DNA by creating double-stranded breaks causing a faulty transcription of the genome which results in cell death or promotion of tumorigenesis. Nature has provided rescue mechanisms — a repair process, to anneal this damage. The common message from these recent studies is that a suppressed testosterone works to thwart the repair process.

  • “Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand breaks repair,” Tarish et al., ScienceTranslationalMedicine, Nov. 2015: Tarish evaluated the DNA repair process based on prostate biopsies in 48 men with localized cancer undergoing radiation. Half had radiation only; in the others radiation was combined with ADT. They demonstrated that androgen suppression interrupted the repair process, thus “explaining the improved response of patients with prostate cancer to radiotherapy after chemical castration.”
  • “Androgen receptor signaling regulates DNA repair in prostate cells,” Polkinghorn et al., Cancer Discovery, Nov. 2013: The research demonstrated that radiation therapy “enhanced DNA repair and decreased DNA damage” and, correspondingly, that androgen suppression inhibits this repair, “providing a potential mechanism by which androgen deprivation synergies with radiotherapy to prostate cancer.” 
  • “A hormone-DNA repair circuit governs the response to genotoxic insult,” Goodwin, Schweizer et al. Cancer Discovery, Nov. 2013: The authors reported their elucidation of the molecular biology underlying the relationship of the radiation induced upregulation of AR signaling, enhanced DNA repair, and therapeutic resistance to radiation. This study points up a mechanism by which radiation has an inherent counterproductive aspect: radiation upregulates the androgen receptor which in turn facilitates the repair of DNA damage.

A hint as to what was forthcoming in later research came in an early work by Vijayakumur et al., Radiology, 1992 Jul, who did a now-unusual check on sequential PSA levels during radiotherapy. The unexpected result was that of 23 patients “four patients had an increase in PSA levels during [a portion of] the course of RT.”  Since PSA expression is promoted by AR activity; the PSA increase in these few men suggested what is now known, that RT upregulates AR activity.

It is currently customary in some regimens to precede radiation with 2 months of ADT. However, early pioneering work on adjuvant hormone suppression by Bolla et al., NEJM  2009, for locally advanced cancer, and again by Bolla, JCO, March 2016, for intermediate- and high-risk disease, demonstrated increases in survival when AS was initiated only on the  first day of radiation and then continued for 6 months. Considering the accelerated action of degarelix (Firmagon) compared to Lupron, it may be possible to gain the benefit of ADT by using degarelex on day one of radiation. [An exception might be for those men with large prostates who need a period of gland shrinkage to facilitate brachytherapy needle placement.]

The Role of ADT Beyond Its Concurrent Use with Radiation Therapy — How Long and Why:

This issue was elegantly explored by Spratt, Polkinghorn, Sawyers et al. in “Androgen receptor upregulation mediates radioresistance after ionizing radiation” [italics mine], Cancer Research, Nov. 2016.

Spratt and colleagues acknowledged the role of ADT as radiosensitizer during RT, but they add “for unknown reasons adjuvant ADT [following RT]  provides further survival benefits,” begging the question as to why, how long, and in which patients. Their research demonstrated that RT durably upregulates the expression of the AR pathway (and its associated repair function) post-therapy “in nearly 20 percent of patients after RT,” and this elevation of AR activity persists beyond the completion of radiotherapy. Considering the clinical heterogeneity inherent in intermediate- and high-risk patients it would be expected that a spectrum of AR upregulation would be present among patients. They cited studies in which men experienced improved survival when ADT was applied only after radiation but had had none during treatment. This suggested that the timing and duration of ADT is important.

During the course of radiation (In preclinical and human studies) they tracked the response of the androgen regulated genes for PSA and its cousin, human glandular kallikrein-2 (hk2). They also monitored the cancer promoting gene fusion product TMPRSS2. Of 227 men with low- or intermediate-risk cancer treated with radiation, 40 showed a rise in these products persisting after the RT was completed.  “… we found that men with increased free-hk2 levels post-ERBT were three times more likely to experience a biochemical failure than those with unchanged or declining hK2 post-treatment,” 17.5% versus 5.3%, respectively. Since the AR governs the expression of thousands of genes, many other genes averse to cancer control may be unregulated in addition to TMPRSS2.

What Are the Clinical Implications of These Studies for the Use of ADT with Radiotherapy?

Much is yet to be learned regarding the upregulation of AR expression by radiation, and significant findings will require testing in clinical trials. The clinical implications of the studies, taken collectively, are best stated in the conclusion of the Spratt article:

“Our results suggest that AR activity during and after ADT/ERBT should be more closely studied with serum and imaging biomarkers to determine their prognostic significance. One potential implication is that adjuvant ADT may only be necessary for men whose tumors upregulate AR as a response to RT.  Alternatively, more potent AR inhibition using second generation ADT might prevent or mitigate the negative consequences of AR upregulation post-RT.”

BOTTOM LINE:  The studies cited here are poignant examples of significant advancements in the understating of the basic mechanisms underlying the relationship of radiation and androgen deprivation.  Successful translation of this basic research into clinical practice is essential for our better controlling prostate cancer while at the same time minimizing adverse effects of treatment.

[I appreciated the opportunity to discuss the Cancer Research article with Dr. Spratt.]

Both comments and pings are currently closed.