An Expert Dissects Recent Research into Radiotherapy for Prostate Cancer

While radiotherapy is a longstanding treatment in the cancer space, questions remain surrounding its use in prostate cancer, according to Anthony D’Amico, MD, PhD.

Anthony V. D'Amico, MD, PhD

Dana-Farber Cancer Institute

D’Amico, a professor of radiation oncology at Harvard Medical School and the chief of genitourinary radiation oncology at the Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts, discussed recent research and current practices regarding the radiotherapeutic management of prostate cancer during a presentation at the 16th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, hosted by Physicians’ Education Resource®, LLC (PER®).

In particular, he spoke about the efficacy of various agents used in the treatment of prostate cancer in combination with radiotherapy, the choice between standard fractionation and hypofractionation, and the optimal use of radiotherapy following surgery in the adjuvant and salvage settings.

Hormone Therapy for Intermediate-Risk Disease

D’Amico first highlighted results from the phase 3 RTOG 0815 trial (NCT00936390) which found that the addition of androgen deprivation therapy (ADT) to radiotherapy yielded a reduced rate of metastasis, reduced cancer-related deaths, and less frequent prostate-specific antigen (PSA) failure among patients with intermediate-risk prostate cancer.¹ In the radiotherapy-alone and experimental arms, 125 and 68 patients, respectively, experienced PSA failure (HR, 0.52; 95% CI, 0.39-0.70; P < .001), 28 and 7 developed distant metastases (HR, 0.25; 95% CI, 0.11-0.57; P < .001), and 10 and 1 experienced cancer-related death (HR. 0.10; 95% CI, 0.01-0.80; P = .007), respectively.

Moreover, D’Amico noted that earlier data from the phase 3 EORTC 22991 (NCT00021450) and GETUG 14 (NCT00104741) trials suggested that ADT delays progression.^2,3 Taken together, these 3 studies support the use of hormone therapy in combination with radiotherapy in intermediate-risk patients.

Hypofractionation

D’Amico next reviewed the current evidence regarding the dosage and scheduling of radiation therapy. He focused on recent findings from the phase 3 CHHiP trial (ISRCTN97182923), which demonstrated the non-inferiority of hypofractionation to standard fractionation.⁴ However, these data also showed that hypofractionation produced a slight increase in late genitourinary toxicities. Therefore, D’Amico recommended careful selection of patients for this dosing schedule to minimize these safety concerns.

Further, he added, ultra-hypofractionation was non-inferior to conventional fractionation in the phase 3 HYPO-RT-PC study (ISRCTN45905321), yielding similar failure-free survival to the conventional schedule, more frequent early adverse effects (AEs), and similar late toxicities among patients with intermediate- to high-risk prostate cancer.⁵

Agents for High-Risk Disease

Regarding patients with high-risk disease, D’Amico first touched on the phase 3 STAMPEDE trial (NCT00268476) examining ADT with or without abiraterone (Zytiga), which supported the abiraterone regimen.⁶ Five-year follow-up showed a median survival of 46 months (interquartile range [IQR], 25-92) in the ADT‐alone group vs 79 months (IQR 33-not reached [NR]) in the abiraterone group. The corresponding rates of survival at 5 years were 41% (95% CI, 37%‐45%) and 60% (95% CI, 50%‐71%), respectively.

He then noted that docetaxel, although unsupported by earlier studies, may reduce prostate-cancer specific mortality in patients with PSA levels under 4 ng/mL, although these data are hypothesis-generating.⁷ This study examined docetaxel in combination with ADT and radiotherapy.

Post-Operative Radiation Therapy

D’Amico concluded with a discussion of the value of adjuvant vs salvage radiotherapy.

The phase 3 RADICALS-RT study (NCT00541047) evaluated radiotherapy timing in 1396 patients and found similar outcomes in both the adjuvant and salvage arms.⁸ The 5-year biochemical progression-free survival (PFS) rate was 85% in the adjuvant group vs 88% in the salvage group (HR, 1.10; 95% CI, 0.81-1.49; P = .56). The proportion of patients free from non-protocol hormone therapy was 93% in the adjuvant group and 92% in the salvage group (HR, 0.88; 95% CI, 0.58-1.33; P = .53).

The smaller phase 3 GETUG-AFU 17 trial (NCT00667069) also did not find any benefit to adjuvant over salvage radiotherapy in terms of event-free survival.⁹ The phase 3 RAVES trial (NCT00860652) failed to prove the non-inferiority of salvage to adjuvant radiotherapy.¹⁰

However, D’Amico noted that all 3 of these trials may have missed a possible benefit to adjuvant therapy in patients with adverse disease pathology at the time of surgery. To this end, a recent retrospective cohort study examined the efficacy of radiotherapy in the adjuvant setting for patients with disease extending beyond the prostate as well as either a Gleason score of 8 to 10 or positive pelvic lymph nodes.¹¹ The findings suggested some clinical benefit to adjuvant radiation, which yielded a significantly lower risk of all-cause mortality than salvage radiation both when patients with positive lymph nodes were excluded (HR, 0.33; 95% CI, 0.13-0.85; P = .02) and included (HR, 0.66; 95% CI, 0.44-0.99; P = .04).

D'Amico suggested that future randomized clinical trials should take these data into account in their design, to thoroughly test for this difference in outcomes. Precise trial design will be crucial to improve the specificity of data and allow physicians to better tailor treatments to each patient, he concluded.

References

1. Krauss DJ, Karrison TG, Martinez AA, et al. Dose escalated radiotherapy alone or in combination with short-term androgen suppression for intermediate risk prostate cancer: outcomes from the NRG Oncology/RTOG 0815 randomized trial. Int J Radia Oncol Biol Phys. 2021;111(suppl 3):S1. doi:10.1016/j.ijrobp.2021.07.039
2. Bolla M, Neven A, Maingon P, et al; EORTC Radiation Oncology Group. Short androgen suppression and radiation dose escalation in prostate cancer: 12-year results of EORTC Trial 22991 in patients with localized intermediate-risk disease. J Clin Oncol. 2021;39(27):3022-3033. doi:10.1200/JCO.21.00855
3. Dubray BM, Salleron J, Guerif SG, et al. Does short-term androgen depletion add to high dose radiotherapy (80 Gy) in localized intermediate risk prostate cancer? Final analysis of GETUG 14 randomized trial (EU-20503/NCT00104741). J Clin Oncol. 2016;34(suppl 15):5021. doi:10.1200/JCO.2016.34.15_suppl.5021
4. Syndikus I, Griffin C, Philipps L. 10-Year efficacy and co-morbidity outcomes of a phase III randomised trial of conventional vs. hypofractionated high dose intensity modulated radiotherapy for prostate cancer (CHHiP; CRUK/06/016). J Clin Oncol. 2023;41(suppl 6):304. doi:10.1200/JCO.2023.41.6_suppl.304
5. Widmark A, Gunnlaugsson A, Beckman L, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019;394(10196):385-395. doi:10.1016/S0140-6736(19)31131-6
6. James ND, Clarke NW, Cook A, et al; STAMPEDE Trials Collaborative Group. Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476). Int J Cancer. 2022;151(3):422-434. doi:10.1002/ijc.34018
7. D'Amico AV, Xie W, McMahon E, et al. Radiation and androgen deprivation therapy with or without docetaxel in the management of nonmetastatic unfavorable-risk prostate cancer: a prospective randomized trial. J Clin Oncol. 2021;39(26):2938-2947. doi:10.1200/JCO.21.00596
8. Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. Lancet. 2020;396(10260):1413-1421. doi:10.1016/S0140-6736(20)31553-1
9. Sargos P, Chabaud S, Latorzeff I, et al. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial. Lancet Oncol. 2020;21(10):1341-1352. doi:10.1016/S1470-2045(20)30454-X
10. Kneebone A, Fraser-Browne C, Duchesne GM, et al. Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial. Lancet Oncol. 2020;21(10):1331-1340. doi:10.1016/S1470-2045(20)30456-3
11. Tilki D, Chen MH, Wu J, et al. Adjuvant versus early salvage radiation therapy for men at high risk for recurrence following radical prostatectomy for prostate cancer and the risk of death. J Clin Oncol. 2021;39(20):2284-2293. doi:10.1200/JCO.20.03714