• Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis

      Gillessen, S.; Choudhury, Ananya; Rodriguez-Vida, A.; Nole, F.; Diaz, E. G.; Roumeguere, T. A.; Daugaard, G.; Loriot, Y.; Saad, F.; McDermott, R. S.; et al. (2021)
      Background: The randomized phase III EORTC-1333-GUCG (NCT02194842) trial compares enzalutamide vs. a combination of Radium 223 and enzalutamide in asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) patients. The premature unblinding of ERA223 (NCT02043678) in Nov 2017 due to a significant increase in the rate of fractures in the combination of abiraterone and Ra223 arm led to the implementation of the mandatory use of bone protecting agents (BPA) in the EORTC-1333-GUCG trial. Skeletal fractures, pathological or not, are a frequent and underestimated adverse event of systemic treatment of advanced prostate cancer. Whether this mandated use of BPA (zoledronic acid or denosumab) would mitigate the risk of fractures in this patient population was unclear. An early safety analysis (Tombal, ASCO, 2019) suggested that the risk of fractures was well controlled in both arms when patients receive BPA. We present here an updated analysis of fracture incidence with longer follow-up. Methods: As of 28/01/2021, a total of 253 patients (134 after making BPA mandatory) were randomized between enzalutamide/Ra223 and enzalutamide. The fracture rate was estimated with the cumulative incidence method in the safety population of 237 (122 after making BPA mandatory) treated patients. Death in absence of fracture was analyzed as competing risk and censoring was applied at last follow-up. Results: Overall, 69.5% of enzalutamide/Ra223 patients (95.2% after making BPA mandatory) and 73.1% of enzalutamide patients (95% after making BPA mandatory) received BPA on treatment: 13.6% in the enzalutamide/Ra223 arm and 21.8% in the enzalutamide arm did not use BPA at registration, but started during protocol treatment and 55.9% and 51.3% respectively, received BPA since entry. At 36.7 months median follow-up in patients without BPA and 23.1 months median follow-up in patients receiving BPA, a total of 39 patients reported a fracture. Among them, 30 patients (20 in enzalutamide/Ra223 arm) did not receive BPA and 9 (4 in the enzalutamide/Ra223 arm) received BPA (see table). Conclusions: The updated safety analysis confirms the early fracture rate results. In the absence of BPA, the risk of fracture is increased when RA223 is added to enzalutamide. Strikingly, in both arms, the risk remains almost abolished by a preventive continuous administration of BPA, thus stressing the importance of complying to international recommendations in terms of giving BPA to mCRPC patients. This study is sponsored by EORTC and supported by Bayer and Astellas.
    • Homologous recombination repair gene mutation characterization by liquid biopsy: a phase II trial of olaparib and abiraterone in metastatic castrate-resistant prostate cancer

      Carr, T. H.; Adelman, C.; Barnicle, A.; Kozarewa, I.; Luke, S.; Lai, Z.; Hollis, S.; Dougherty, B.; Harrington, E. A.; Kang, J.; et al. (2021)
    • Safety and overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (Ra-223) plus subsequent taxane therapy

      Higano, C. S.; Harshman, L. C.; Dizdarevic, S.; Logue, John P; Richardson, T.; George, S.; Song, D.; de Jong, I. J.; Tomaszewski, J.; Saad, F.; et al. (2020)
      Background: Ra-223, a targeted alpha therapy, showed a survival benefit and favorable safety profile over 3 years’ (yrs) follow-up in mCRPC pts (ALSYMPCA trial). REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of long-term Ra-223 safety in routine clinical practice in mCRPC pts (planned 7-yr follow-up). Methods: This analysis, based on the second prespecified interim analysis (data cutoff 3-20-2019) of REASSURE (N = 1465), evaluated safety/OS in the pt subset that was chemotherapy-naïve at Ra-223 administration but received subsequent taxane therapy any time after Ra-223 completion. Results: 182 pts received taxane therapy after Ra-223. Most (58%) had unresected primary tumors, 69% had ?6 metastases, 99% received prior systemic anticancer therapy (Table). 143 (79%) completed 5 or 6 Ra-223 injections. Subsequent anticancer therapies included docetaxel (95%), enzalutamide (25%), cabazitaxel (24%), abiraterone (12%), lutetium-177-prostate-specific membrane antigen (4%), and sipuleucel-T (1%). During/up to 30 days after taxane therapy, 15 pts (8%) had grade 3/4 hematologic adverse events: anemia (erythropenia) (n = 11, 6%), neutropenia (n = 3, 2%), and thrombocytopenia (n = 2, 1%). Median OS was 24.3 (95% CI: 20.9–27.5) months from Ra-223 initiation and 11.8 (95% CI: 10.6–14.1) months from subsequent taxane initiation. Conclusions: In this cohort where Ra-223 was integrated prior to taxane therapy, most pts received multiple subsequent anticancer therapies. It appears that sequencing of multiple treatment modalities with different mechanisms of action may contribute to improved OS. Taxane therapy in routine clinical practice in pts previously treated with Ra-223 had acceptable hematologic safety/tolerability profiles.
    • Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial

      Parker, C. C.; Clarke, Noel W; Cook, A. D.; Kynaston, H. G.; Petersen, P. M.; Catton, C.; Cross, W.; Logue, John P; Parulekar, W.; Payne, H.; et al. (2020)
      Background: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. Methods: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ?10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ?0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. Findings: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). Interpretation: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy.