SUO - AUA 2020 Summer Webcast: Three Papers in the Past Year that Have Changed My Practice: Prostate Cancer

( The Society of Urologic Oncology (SUO) held a virtual meeting on Saturday, July 18, 2020, in place of the usual meeting held at the American Urological Association (AUA) Annual Meeting. This virtual meeting was divided into sessions on bladder cancer, kidney cancer, and prostate cancer. In the session on prostate cancer, Keith Kowalczyk, MD, presented three papers in prostate cancer which most significantly changed his practice in the past year.

First, after acknowledging the increasing role of prostate magnetic resonance imaging (MRI) for prostate cancer diagnosis and identification of appropriate candidates for active surveillance, he highlighted recent data from Dr. Behfar Ehdaie’s group assessing whether MRI is sufficient to detect disease progression in patients on active surveillance. This single-center study from Memorial Sloan Kettering Cancer Center in New York examined 207 men with National Comprehensive Cancer Network (NCCN) very low and low-risk disease on confirmatory biopsy. These men subsequently had a repeat MRI and biopsy. The authors found that 64% of patients had no evidence of change in the MRI. However, on biopsy, 48% had GG2 disease or greater with GG2 in 32%, GG3 in 15%, and GG4 in 1%. In multivariable logistic regression analysis, the MRI score was not predictive of biopsy reclassification. Further, an approach using biopsy only on the basis of MRI suspicion would miss many clinically significant cancers (169 per 1000 men). This held true for men with baseline normal MRI (PIRAD <3) and abnormal MRI. He concluded that a lack of change in digital rectal examination (DRE) or MRI does not obviate the need for routine surveillance biopsy. Thus, for patients on surveillance, both MRI and biopsy should be performed at routine intervals.

Second, Dr. Kowalczyk examined data on adjuvant radiotherapy. He began by highlighting the SWOG 8794 data which showed the benefit of adjuvant radiotherapy when compared to a late salvage strategy. However, this approach is poorly adopted due to concerns of overtreatment and toxicity. This year, three randomized controlled trials (RCT) were presented assessing adjuvant vs early salvage radiotherapy  (RADICALS-RT, GETUG-AFU-17, and RAVES). A pre-planned aggregate data meta-analysis deemed the ARTISTIC collaboration provided a synthesis of these data. This adaptive meta-analysis was designed based on a primary outcome of prostate-specific antigen (PSA)-driven event-free survival comprising PSA ≥0.4ng/mL and rising following radiotherapy, clinical/radiological progression, initiation of non-trial treatment, death from prostate cancer following postoperative radiotherapy, and PSA ≥2.0ng/mL at any point following randomization.

Across the three included studies, 1074 patients were randomized to adjuvant radiotherapy while 1077 were randomized to an early salvage radiotherapy strategy. Among those randomized to early salvage radiotherapy, the vast majority did not require salvage treatment (63%) demonstrating the significant overtreatment associated with an adjuvant approach. As of a data cut-off of August 2019, there were 245 events. Event-free survival was non-significantly different between these approaches, with an effect estimate that favored the early salvage approach (hazard ratio 1.12, 95% confidence interval 0.88 to 1.42). As expected due to the large proportion of patients in the early salvage arm who did not receive radiotherapy, toxicity was lower in that arm.

Dr. Kowalczyk concluded that these data support the equivalent oncologic outcomes for adjuvant and early salvage radiotherapy in men with intermediate-risk of recurrence with toxicity spared in the 63% of men who didn’t require salvage. Ongoing follow-up will be necessary to assess more clinically relevant outcomes such as metastasis-free survival. However, he suggested that he would still offer adjuvant radiotherapy to particularly high-risk men.

Finally, Dr. Kowalczyk highlighted the PROfound study of olaparib in patients with metastatic castration-resistant prostate cancer. This represents one of the first Phase III trials of molecularly targeted treatment in advanced prostate cancer. He began by discussing the biology of PARP inhibitors which target tumors with germline mutations in DNA damage repair mechanisms (including BRCA1, BRCA2, and ATM).

The PROfound study recruited men with metastatic castrate-resistant prostate cancer who had progressed on previous abiraterone acetate or enzalutamide administered at the time of non-metastatic castrate-resistant prostate cancer or at the time of metastatic castrate-sensitive prostate cancer. Patients with prior taxane exposure were allowed. The investigators then used an investigational assay to identify alterations in one of 15 pre-specified genes involved in homologous recombination repair (BRCA 1/2, ATM, BRIP1, BARD1, CDK12, CHEK 1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L). The authors derived two study cohorts: Cohort A had alterations in BRCA1, BRCA2, or ATM while Cohort B had alterations in any of the other 15 included genes. In both cohorts, patients were randomized 2:1 to olaparib vs. abiraterone or enzalutamide with a primary outcome of imaging-based progression-free survival.

In the primary analysis, assessing cohort A, olaparib demonstrated significant improvements in progression-free survival (7.4 vs. 3.6 months; hazard ratio 0.34), overall survival (18.5 vs. 15.1 months; hazard ratio 0.64), objective response rates (33% vs. 2%; odds ratio 20.86), and time to pain progression (hazard ratio 0.44). These benefits were seen in spite of significant cross-over (81%), suggesting that earlier use of poly-ADP ribose polymerase (PARP) inhibition provides significant benefit compared to later use. The use of olaparib was associated with increased rates of adverse events, including death in 4%.

Dr. Kowalczyk concluded that olaparib provided significant oncologic and symptomatic benefits, particularly in men with BRCA1, BRCA2, and ATM mutations. Smaller benefits were seen in men with other mutations. Moving forward, this trial highlights the importance of germline testing for men with advanced prostate cancer.

Presented by: Keith Kowalczyk, MD, Director of Urologic Oncology, MedStar Georgetown University Hospital, Washington, DC, USA 

Written by: Christopher J.D. Wallis, MD, PhD, Urologic Oncology Fellow, Vanderbilt University Medical Center, Nashville, Tennessee, USA, Contact: @WallisCJD on Twitter at the Society of Urologic Oncology (SUO) - American Urologic Association (AUA) 2020 Summer Webcast  Program, July 18, 2020