ASCO GU 2024: Discussant: Androgen Deprivation & Radiation Therapy: Going Further, Together

(UroToday.com) The 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium featured a prostate cancer session and a discussant presentation by Dr. Neha Vapiwala discussing going further together with androgen deprivation and radiation therapy. Dr. Vapiwala started by noting that the word “synergy” comes from the Greek word synergia and is defined as “working together”. There are two theories as to how/why ADT and radiation therapy work together: Spatial cooperation and In-field cooperation, as highlighted in the following figure:

For spatial cooperation, Dr. Vapiwala postulates that would we not expect surgery to have a comparable effect with ADT? For in field cooperation, she notes that “true” radiosensitizers lack independent cytotoxicity. For ADT and radiation therapy, this is a synergistic biologic combination, with co-dependent, complex cytotoxic interactions: 

Dr. Vapiwala notes that ADT + radiation therapy is a winning combination with robust level 1 evidence demonstrating that, compared to lower “conventional” dose radiation therapy alone:

• Dose-escalated radiation therapy, via various modalities, improves biochemical control/progression free survival, distant metastases, and freedom from salvage therapies. However, there is no overall survival impact and greater late gastrointestinal and genitourinary toxicity
• The addition of ADT to lower dose radiation therapy improves overall survival. However, this is at the expense of systemic toxicities (fatigue, weight gain, osteoporosis, insulin resistance, and risk of cardiovascular disease)

But, are ADT and radiation therapy happy together or better off alone? Is ADT compensating for an inadequate radiation therapy dose? Can more radiation therapy:

• Maintain the benefit of combination therapy in the absence of ADT?
• Provide an acceptable side effect profile?
• Obviate ADT-related quality of life detriments?
• What about some ADT versus no ADT in intermediate-risk patients?

The GETUG 14 trial assessed dose escalated radiation therapy (80 Gy) +/- 4 months of ADT, but this trial was slow to accrue and thus was closed at enrolment of 377 out of 450 patients among intermediate risk prostate cancer. However, after a median follow-up of 84 months, ADT increased event free survival versus dose escalated radiation therapy alone, with no difference in overall survival or grade 3+ toxicities. Based on this trial, some ADT is still good.

Dr. Vapiwala then discussed the NRG/RTOG 0815 trial assessing dose escalated radiation therapy +/- 6 months of ADT in intermediate risk prostate cancer, with ADT resulting in more acute grade >= 3 adverse events (12% vs 2%, p < 0.001) and more clinically meaningful declines in patient-reported outcomes for EPIC hormonal sexual domains. Again, in this trial, there was no overall survival benefit. Based on the above, is overall survival the only metric that counts? These patients often have improved distant metastasis and prostate cancer specific mortality outcomes, with no difference in overall late grade >=3 adverse events, and quality of life differences that are transient (resolve in <1 year). As such, it is important to individually counsel patients regarding the risks and benefits of ADT + dose escalated radiotherapy.

Perhaps a bit of both (ADT and radiation therapy) is just right. The PCS III trial randomized intermediate risk patients to dose escalated radiation therapy (76 Gy) versus dose escalated radiation therapy + 6 months of ADT versus lower dose radiation therapy (70 Gy) + 6 months of ADT. With a primary end point of biochemical failure and secondary outcomes of overall survival and toxicity, this trial found that over a median follow-up of 11.3 years, ADT significantly lowered biochemical failure, progression, and prostate cancer death versus dose escalated radiation therapy alone. There was no overall survival difference, but dose escalated radiation therapy had a higher late grade >=2 gastrointestinal toxicity (16% versus 5.3%, p < 0.001). Thus, in this trial, ADT + 70 Gy is the “sweet spot” for intermediate risk prostate cancer disease control and GI toxicity.

Moving to high risk prostate cancer, there are several trials that have looked at short term versus long-term ADT:

Dr. Vapiwala then discussed the DART 01/05 trial, which was an open-label, phase 3, randomized, controlled trial which was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. Among 355 intermediate and high risk prostate cancer patients, treatment was dose escalated radiation therapy (76-82 Gy) + 4 vs 28 months of ADT. DART 01/05 found that the 5-year overall survival was improved with long-term ADT, with no increase in radiotherapy toxicity, but a significant increase in non-fatal cardiovascular events. At 10 years of follow-up, there was no difference in these treatment regimens for overall survival, but there was a clinically relevant 12% benefit in hazard ratio, with no increase in cardiovascular events.

This introduction led into the discussion of GETUG-AFU 18, which was a randomized trial of dose escalation (80 vs 70 Gy) combined with long-term androgen deprivation in high-risk prostate cancer. Eligible patient had high-risk (cT3-T4 or PSA≥ 20 ng/ml or Gleason score ≥ 8-10) prostate adenocarcinoma with negative lymph-nodes status on CT-scan or MRI. Patients were either pN0 or cN0 up to 15 mm lymph node diameter on CT or MRI. Patients were randomly assigned 1:1 to dose-escalated radiotherapy (80 Gy) or conventional-dose (70 Gy) with 3 years of ADT in both arms. Over a median follow-up of 9.5 years (95% CI 9.4 – 9.7), the biochemical or clinical progression-free survival was significantly improved in the dose-escalated radiotherapy arm compared with conventional radiotherapy arm (HR 0.56, 95% CI, 0.40-0.76, p = 0.0005):

Additionally, there were also observed significant differences in prostate cancer-specific survival (HR 0.48, 95% CI, 0.27-0.83, p = 0.0090) and overall survival (HR 0.61, 95% CI, 0.44-0.85, p = 0.0039) favoring dose-escalated radiation therapy. Regarding late toxicities, there was no significant difference between arms for ≥ grade 2 toxicity with dose-escalated radiotherapy and conventional radiotherapy.

Overall, it is important to consider the patient and not just the prostate cancer. Looking back at the DARK 01/05 trial, Dr. Vapiwala emphasized that among 354 patients, 3% of deaths were prostate cancer and 21% were non-prostate cancer deaths. This included 9% from second cancers (smoking related, outside of the radiation therapy field), and a 6% cardiovascular disease risk (32% from long-term ADT and 17% from short term ADT).

Dr. Vapiwala then discussed the patient reported outcomes from the FORMULA 509 trial, which previously demonstrated that for patients with a PSA >0.5 ng/mL after radical prostatectomy receiving salvage radiation and 6 months of GnRH agonist, the addition of abiraterone acetate + prednisone and apalutamide improved metastasis-free survival compared to bicalutamide (HR 0.32, 95% CI 0.13-0.84). Dr. Vapiwala compared this trial to the ACIS trial,² which was a double blind trial of 982 patients with mCRPC assessing ADT + indefinite apalutamide + abiraterone versus placebo + abiraterone. In ACIS, the combination improved radiographic progression free survival (HR 0.70, p < 0.001), with comparable treatment-emergent and serious treatment emergent adverse events between the groups. Furthermore, quality of life outcomes were comparable between the groups.

Dr. Vapiwala notes that the FORMULA 509 trial had validated instruments for their patient reported outcomes assessment with a strong completion rates. From baseline to end of treatment, both arms demonstrated clinically meaningful declines in EPIC-26 hormonal domain (median change -15 bicalutamide; -15 abiraterone acetate + prednisone/apalutamide). But, from end of treatment to 1 year after treatment patient-reported health-related quality of life improved to near baseline for EPIC-26 hormonal function (bicalutamide median score baseline: 95, end: 75, 1 year: 90; abiraterone acetate + prednisone/apalutamide a baseline: 95, end: 75, 1 year: 90):

Similar results were also noted for EPIC-26 sexual function, although at baseline only 21% of patients had erections firm enough for intercourse: 

Thus, it appears that after 1 year, side effects assessed in this trial diminished. However, there was no blinding in this trial, which may influence patient belief that more intense treatment is better and/or worth the side effects. 

Dr. Vapiwala concluded her discussant presentation with the following take-home points:

• The synergy between radiation therapy and ADT is real: biologically, clinically, and professionally
• Therapy selection is important: how much (duration) and how (combination) given that in localized prostate cancer, timing of ADT + radiation therapy appears to matter
• Those with the greatest tumor burden are most apt to benefit and experience adverse events
• The risk benefit ratio in healthier and lower risk patients places a premium on patient selection and informed decision making
• Together = patients, providers, researchers, and all who are supporting them

Presented by: Neha Vapiwala, MD, FACR, FASTRO, FASCO, Penn Medicine, Philadelphia, PA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25^th – January 27^th, 2024 

References:

1. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy and risk-adapted androgen deprivation in localized prostate cancer (DART 01/05): 10-year results of a phase 3 randomized controlled trial. Lancet Oncol. 2022 May;23(5):671-681.
2. Saad F, Efstathiou, Attard G, et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): A randomized, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2021 Nov;22(11):1541-1559.