Additionally, the PROFOUND study showed the superiority of olaparib versus antigen receptor signaling inhibitors in patients with a similar prior treatment history but with genetic alterations in homologous recombination DNA repair-related genes (HRR).2
In this study, the authors hypothesized that patients harboring HRR defects might respond differently to standard therapy (cabazitaxel, abiraterone, and enzalutamide) for metastatic castrate-resistant prostate, leading to different outcomes than those shown in the CARD trial.
The PROREPAIR-B (NCT03075735) trial is a prospective multicenter study aiming to demonstrate the prognostic role of deleterious germline mutations in gHRR genes and the benefit of 1st, 2nd and subsequent therapy lines for patients with metastatic castrate-resistant prostate cancer patients.3 The outcomes with first- and second-line treatment were reported in this trial.3 Patients with BRCA 2 mutations had a deleterious impact on MCRPC outcomes that may be affected by the first line of treatment that was used, as can be seen in Figure 1.
The objectives of this study were to evaluate radiographic progression-free survival, clinical progression-free survival, and overall survival in patients enrolled in the PROREPAIR-B trial who met the CARD study eligibility criteria and who received either cabazitaxel, abiraterone or enzalutamide.
The results of this trial show that 95 out of 419 MCRPC patients included in the PROREPAIR-B study met the original CARD eligibility criteria and received cabazitaxel (n=60) or abiraterone or enzalutamide (n=35), with 14 patients who were gHRR carriers. Eight of the gHRR patients were treated with cabazitaxel, and 6 were treated with either abiraterone or enzalutamide.
Interestingly, visceral metastases were more frequent among patients treated with cabazitaxel. Additionally, ECOG 2, M1 at diagnosis, abiraterone as a first-line treatment, and prior radiographic disease progression (all p<0.05) were more frequent in the patients in this trial than in the original CARD study.
Figure 1 – Cancer-specific survival in BRCA2 carriers and non-BRCA 2 carriers by treatment sequence (A) patients treated with an androgen receptor signaling inhibitor followed by a taxane; and (B) patients treated with a taxane followed by an androgen receptor signaling inhibitor.
Overall, cabazitaxel was superior to both abiraterone and enzalutamide in terms of radiographic progression-free survival (median 6 months vs. 3.7 months, p=0.03) as seen in figure 2, clinical progression-free survival (median 4.4 months vs. 3,4 months, p=0.01) and PSA50 responses (39% vs. 17%, p=0.027). There were no differences in the overall survival rates.
Figure 2 – Radiographic progress free survival:
When assessing the results of the subgroup analyses, they were quite like the ones reported in the CARD study. In this series, gHRR carriers had a significantly worse prognosis than non-carriers, as shown in Figure 3.
The Cox multivariable regression models adjusted for imbalances and CARD grouping factors confirmed a significant interaction between treatment and gHRR status, showing that the benefit previously shown by cabazitaxel was not observed in patients with gHRR.
Figure 3 – Radiographic progression-free survival by gHRR status:
The authors concluded that these results confirm the benefit of cabazitaxel treatment over a second androgen receptor (abiraterone or enzalutamide) in unselected mCRPC patients. However, the outcomes in gHRR carriers are poor with any type of treatment, which supports the need for novel therapies in this setting.
Presented by: Dr. N. Romero-Laorden, H.U. La Princesa, Spain
Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHanan at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.
- de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. The New England journal of medicine 2019; 381(26): 2506-18.
- de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. New England Journal of Medicine 2020; 382(22): 2091-102.
- Castro E, Romero-Laorden N, Del Pozo A, et al. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2019; 37(6): 490-503.