SES AUA 2022: Optimizing Therapy for Locally Advanced Prostate Cancer

(UroToday.com) The 2022 Southeastern Section of the AUA’s annual meeting included a state-of-the-art lecture by Dr. Brian Chapin discussing optimizing therapy for locally advanced prostate cancer. Dr. Chapin started by highlighting that the disease states of prostate cancer have become quite detailed, based on castration status and line of therapy received:

However, particularly in the locally advanced setting commonly leading to disease recurrence, is it possible to alter the disease course with an intervention? Is it possible to cure these patients? Prolong survival? Delay time to systemic therapy?

High-risk disease is defined based on digital rectal examination, PSA, and pathology, with two commonly utilized definitions:

1. NCCN
   1. High risk: cT3a, or Gleason Grade Group 4 or 5, or PSA > 20 ng/mL
   2. Very high risk: cT3b-4, or primary pattern 5, or >4 cores of Gleason Grade Group 4 or 5
2. D’Amico: cT2c-T3a, or Gleason >=8, or PSA > 20 ng/mL

Ultimately, stratification into high and very high-risk groups provides meaningful delineation for risk of biochemical recurrence, metastasis, and cancer specific mortality:

Dr. Chapin emphasized that locally advanced disease equals high risk disease, but not all high-risk disease is locally advanced disease. But, what we are treating may not truly be high risk, given that Gleason 8 disease on biopsy may not correlate with radical prostatectomy pathology, as highlighted by work from Duke, the NCDB, and a MD Anderson Cancer Center/Cleveland Clinic/Johns Hopkins University collaborative:

 Ultimately, risk stratification and treatment are moving targets, particularly with stage migration from increased utilization of PSMA staging in high-risk prostate cancer. The proPSMA trial was a multi-center, two-arm randomized controlled trial among men with histologically confirmed prostate cancer who were being considered for curative intent radical prostatectomy or radiotherapy.¹ Patients were randomly assigned in a 1:1 ratio to either conventional imaging performed using bone scan and CT or Ga-68 PSMA-11 PET/CT.

The primary study outcome was accuracy of first-line diagnostic imaging for the identification of either pelvic nodal or distant metastatic disease. Among 302 men, of which the reference standard was possible in 295 of men, PSMA PET-CT resulted in detection of any metastasis in 23% of cases, compared to 7% of cases for conventional imaging. However, Dr. Chapin notes that there are several unanswered questions with regards to the proPSMA data, including:

1. Are these patients with metastasis now “oligometastatic”?
2. Do these patients even benefit from local therapy?

With regards to treatment options for high- or very-high risk patients, Dr. Chapin notes that the NCCN guidelines give external beam radiotherapy a category 1 recommendation, whereas surgery has a category 1 to 2B recommendation:

When trying to decide which treatment is better, Dr. Chapin notes that there are inherent biases, as highlighted with the following examples of discussions with urology and radiation oncology colleagues:

• Urologist: “salvage radical prostatectomy is near impossible”
• Radiation Oncologist: “every post radical prostatectomy patients gets radiotherapy anyway”
• Urologist: “secondary cancers are a real issue”
• Radiation oncologist: “radiotherapy side effects don’t occur”

Looking closer at the available data, the following table highlights studies assessing ADT +/- RT for high risk prostate cancer:

The ProtecT trial randomized 1,643 men with localized prostate cancer to active monitoring, radiotherapy, or surgery.² However, notably there were very few high-risk patients, including no patients with cT3 disease and only 37 patients with Gleason 8-10 disease (2%). The SPCG-4 trial randomized men with localized prostate cancer to surgery or observation,³ noting with 18-year follow-up no difference in relative risk reduction for death, prostate cancer-specific mortality, or metastasis, however with a relative risk reduction for ADT use favoring surgery (relative risk reduction 0.45, 95% CI 0.31-0.65):

The PIVOT trial⁴ randomized men with localized prostate cancer to prostatectomy versus observation and with long-term follow-up, there was a benefit favoring surgery for improved local and systemic disease progression, however no difference in prostate specific mortality among all patients and when restricting to only high-risk patients:

When comparing surgery to radiation for high-risk patients, the studies to date are inherently biased and thus data/results must be interpreted cautiously. Patients with high-risk prostate cancer undergoing radical prostatectomy, still have significant 10-year secondary therapy, 10-year metastasis, and 10-year prostate cancer-specific mortality rates:

But, Dr. Chapin notes that with a “glass is half full” approach, it is perhaps notable that 35-40% of these patients will be spared any secondary therapy at 10 years after undergoing radical prostatectomy as their primary treatment.

Androgen deprivation therapy is commonly used with radiotherapy for 18-36 months had has several common and notable effects on quality of life, including (i) fatigue, (ii) hot flashes, (iii) decreased libido and erectile dysfunction, (iv) gynecomastia, (v) psychological/emotional/cognitive impairment, (vi) comorbidities such as coronary artery disease and diabetes mellitus, and (vii) anemia, lipid dysfunction. Additionally, the longer you wait after radiotherapy, the more second cancer the patient is susceptible to, with a 10-14 year relative risk of 1.6, and a >15 year relative risk of 1.91:

Based on data from SPCG7, patients that had radiotherapy in combination with hormonal therapy (versus hormonal therapy alone) had a noteable increase in secondary malignancies at ~10 years after starting therapy.

With regards to personalization of care, Dr. Chapin notes that the clinical cases dictate treatment. There are several situations where surgery or radiation may be preferred:

• Surgery preferred: IBD/Crohns disease/UC, pre-existing lower urinary tract symptoms/retention, Lupus/scleroderma, young age (debatable), and prior pelvic radiotherapy
• Radiation preferred: non-surgical candidate/extensive comorbidities, multiple prior/complex abdominal surgeries, unwilling to accept potential for stress urinary incontinence, cT4 requiring a cystoprostatectomy or pelvic exenteration

Dr. Chapin notes that the way we think about the personalized approach to prostate cancer therapy involves seeing a patient in the clinic and assessing them on a number of factors (clinical features, genetics, genomics, serum markers, receptors, induced responses, and selection pressures) and then developing a personalized approach to their treatment plan:

However, does sequence and subsequent therapy matter and does where you start predict where you will end up?

 Over the last several years, there has been some clarity as to the timing of adjuvant versus salvage radiotherapy. Three randomized controlled trials were contemporaneously designed and began accruing to assess the comparison of adjuvant and early salvage radiotherapy strategies, each with a different primary outcome: time free of metastasis in RADICALS-RT,⁵ event-free survival (GETUG-AFU 17),⁶ and biochemical progression (RAVES).⁷ As an intermediate step, there was a planned aggregate data meta-analysis (ARTISTIC),⁸ which showed no difference in event-free survival between adjuvant versus early salvage radiotherapy:

 Dr. Chapin notes that there are issues with generalizability when assessing randomized trials for adjuvant versus salvage radiotherapy, including: (i) more favorable risk patients were included (the majority of which were Gleason 7 disease), (ii) <20% had Gleason 8-10 or pT3b disease, and (iii) <5% had pathologic node-positive disease. As such, he suggests that shared decision-making still has a role in adjuvant therapies.

With regards to adjuvant ADT in node-positive prostate cancer, the ECOG 3886 trial randomized 98 patients with node-positive to disease to immediate ADT versus observation.⁹ Immediate ADT was associated with improved overall survival (85% vs 64%), disease-specific survival (93% vs 68%), and progression-free survival (77% vs 43%). As follows is the Kaplan Meier curve for prostate cancer-specific survival:

Salvage lymph node dissection has also continued to gain support in appropriate clinical scenarios, however Dr. Chapin notes that it is difficult to define success, it is debatable if there is any benefit aside from prognostication (does it help us decide on ADT? Radiation?), and just because we see it does not mean we need to excise it. Long-term outcomes of patients treated with salvage lymph node dissection for nodal recurrence until recently were essentially unknown. Bravi et al.¹⁰  undertook a multi-institutional approach to assess these long-term outcomes, including 189 patients who experienced PSA rise and nodal-only recurrence after radical prostatectomy and underwent salvage lymph node dissection at 11 centers between 2002 and 2011. Recurrences were detected with either ¹¹C-choline or ⁶⁸Ga PSMA. The primary outcome was cancer-specific mortality, and the secondary outcomes were overall mortality, clinical recurrence, biochemical recurrence, and ADT-free survival after salvage lymph node dissection. There were 110 and 163 patients experienced clinical recurrence and biochemical recurrence, respectively, with clinical recurrence-free and biochemical recurrence-free survival at 10 years of 31% and 11%, respectively:

After salvage lymph node dissection, a total of 145 patients received ADT, with a median time to ADT of 41 months. Importantly, additional therapy was warranted in >60% of patients within 6 months of salvage lymph node dissection. At a median follow-up for survivors of 87 (IQR 51 to 104) months, 48 patients died, of which 45 died from prostate cancer. At multivariable analyses, patients who had PSA response after salvage lymph node dissection (HR 0.45; p = 0.001), and those receiving ADT within 6 months from salvage lymph node dissection (HR 0.51; p = 0.010) had lower risk of death from prostate cancer.

 Treatment of oligometastasis has also recently been generating great interest. Two important phase 2 trials, STOMP¹¹ and the ORIOLE trial,¹² have demonstrated biochemical recurrence-free survival and progression free survival for patients undergoing metastasis directed therapy/SABR versus observation:

For the remainder of his presentation, Dr. Chapin highlighted several important high-risk prostate cancer clinical trials. Generally, the neoadjuvant/presurgical preoperative clinical model for designing clinical trials includes a patient fit for surgery with a low cure rate with surgery, treated with a neoadjuvant drug(s) for 3-12 months, followed by a radical prostatectomy:

The CALGB 90203 (Alliance) trial is assessing neoadjuvant chemohormonal therapy prior to radical prostatectomy in high-risk prostate cancer. Patients are randomized to 6 cycles of chemohormonal therapy followed by surgical intervention versus surgical intervention:

The PROTEUS trial is an international multicenter study and enrolling ~2000 patients with localized/locally advanced high-risk/very high-risk prostate cancer who are candidates for radical prostatectomy with pelvic lymph node dissection over 3 years at > 203 sites in 18 countries. Stratification variables include: Gleason score (7 vs ≥ 8), pelvic node status (N0 vs N1), international region. Randomization is 1:1 to apalutamide (240 mg/day) + ADT or placebo + ADT. Patients receive 6-month neoadjuvant treatment followed by radical prostatectomy and then 6 months of adjuvant treatment.

The PROTEUS study design is as follows:

The primary end points are pathologic complete response rate and metastasis-free survival; in addition to metastasis-free survival based on conventional imaging, metastasis-free survival based on PSMA PET or conventional imaging will be assessed as a separate end point. The SPCG-15 trial is assessing radical prostatectomy + extended pelvic lymph node dissection versus radiotherapy + 24 months of ADT, with a primary endpoint of prostate cancer specific survival and secondary endpoints of metastasis free survival and quality of life. To date (as of June 2021), 760 patients have been enrolled, with 80% of patients cT3 and a median PSA of 13 ng/mL.

Decipher is a prognostic marker and has also recently been incorporated into clinical trials. Decipher is a 22 gene classifier for risk stratification based on radical prostatectomy specimen analysis with prognostication for metastasis. However, there is no data on predictive ability, although it is currently undergoing prospective evaluation. The PREDICT-RT trial (NRG-GU009) is using Decipher to stratify patients followed by subsequent randomization, as highlighted in the following trial schema:

Finally, the genomic umbrella neoadjuvant study (GUNS) trial is evaluating conditional lethality of targeted therapy. Patients with high-risk localized prostate cancer will undergo genomic profiling and an LHRH agonist + apalutamide for 8 weeks, followed by assignment to androgen receptor axis treatment if there are no targetable aberrations (SPOP, ETS; Group 1) or loss of tumor suppressor genes (PTEN, Rb, p53 mutations; Group 2) or DDR alterations (Group 3), or hypermuted/MSI/Lynch syndrome (Group 4). The trial outline is as follows and mirrors a STAMPEDE platform design approach:

Dr. Chapin concluded his presentation discussing the optimization of therapy for locally advanced prostate cancer with the following summary points:

• What we need is improved radiation targeting, improved surgical techniques, and improved combination therapies
• But, we also need improved staging with both local and whole body modalities (with evaluation of improved staging and treatment selection to assess for clinical benefit), and improved biology subtyping in order to predict which treatment is most effective

Presented By: Brian F. Chapin, MD Anderson Cancer Center, Houston, TX 

Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 86th Annual Meeting of the Southeastern Section of the American Urological Association, San Juan, PR, Mar 16 – 19, 2022

References:

1. Hofman MS, Lawrentschuk N, Francis, RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): A prospective, randomized, multicentre study. Lancet 2020 Apr 11;395(10231):1208-1216.
2. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med 2016;375(15):1415-1424.
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7. 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.
8. Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for the treatment of localized and locally advanced prostate cancer: A prospectively planned systematic review and meta-analysis of aggregate data. Lancet 2020 Oct 31;396(10260):1422-1431.
9. Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006 Jun;7(6):472-479.
10. Bravi CA, Fossai N, Gandaglia G, et al. Long-term Outcomes of Salvage Lymph node dissection for nodal recurrence of prostate cancer after radical prostatectomy: Not as Good as Previously Thought. Eur Urol 2020 Nov;78(5):661-669.
11. Ost P, Reynders D, Decaestecker K, et al. Surveillance of Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin Oncol 2018 Feb 10;36(5):446-453.
12. Phillips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol 2020 Mar 26;6(5):650-659.