Dr. Taplin notes that the glass is both half full and half empty – mCRPC patients are living longer compared to pre-2010, but more than 50% of patients with mCRPC die within 3 years.1 Despite advances in targeted therapy for mCRPC, the clinical impact has been modest.
Several recent advances:
- The genomic landscape of mCRPC has been defined
- DNA damage repair genes (ie. BRCA1/2) have a predictive response for PARP inhibitors
- Many compounds remain in clinical testing
- Timing of molecular testing
- Availability of liquid or tissue material
- Tumor heterogeneity
- Lack of drugs for most tumor drivers
- Data sharing
- 85% of cancer care is delivered in the community setting
TOPARP-B randomized 1:1 98 mCRPC patients to 400mg or 300mg of olaparib BID, with a primary endpoint of response rate was defined as radiological response (RECIST 1.1) and/or PSA50% fall and/or CTC count conversion (Cellsearch; ≥5 to < 5), confirmed after 4-weeks. The overall response rate was 54% (95%CI 39-69%), meeting threshold for primary endpoint) in the 400 mg cohort and 39% (95%CI 24-54%) in the 300 mg cohort. Over a median follow-up of 17.6 months, the overall median PFS (mPFS) was 5.4 months. Subgroup analyses per altered gene identified indicated response rates for BRCA1/2 of 83% (mPFS 8.1 months), PALB2 57% (mPFS 5.3 months), ATM 37% (mPFS 6.1 months), CDK12 25% (mPFS 2.9 months), and others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (mPFS 2.8 months). The highest PSA50% response rates were observed in the BRCA1/2 (77%) and PALB2 (67%) subgroups.
Dr. Taplin notes that this study confirms PARP inhibition is effective in patients with DNA damage repair altered tumors in heavily pre-treated patients, including 35% of BRCA1/2 patients responding after more than 1 year of treatment. Furthermore, she highlights that the data on gene subgroups is helpful for counseling patients. However, on the contrary, 711 patients were screened and only 92 patients were evaluable (13%). Although response rates were better with 400 mg olaparib, 37% of patients were dose reduced to 300mg secondary to adverse effects. Finally, the median time on treatment for the whole cohort was only 5.5 months. Dr. Taplin states that we must await the results of phase 3 trials.
The randomized phase II study of cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic CRPC randomized 95 patients to receive cabazitaxel (Arm A) or androgen receptor targeted therapy (Arm B, abiraterone or enzalutamide by investigator choice), with cross over at progression. The primary objective was to determine the clinical benefit rate (defined as PSA decline ≥50% (PSA50), objective response, or stable disease ≥ 12 weeks). Patients receiving cabazitaxel had a higher clinical benefit rate (88%) compared to patients receiving abiraterone or enzalutamide (70%; p = 0.043), however there was no difference between the arms for time to first-line PSA progression (HR 0.94, 95% CI 0.57-1.56) and no difference in overall survival after adjusting in a multivariable model (HR 0.77, 95% CI 0.41-1.44).
Baseline ctDNA fraction > 15% (median) was associated with shorter 1st-line progression-free survival (median 2.8 vs 8.4 months, HR 2.54, p < 0.001) and overall survival (median 14.0 vs 38.7 months, HR 2.64, p = 0.001).
Dr. Taplin notes that there are many different ways to define poor prognosis mCRPC:
The challenges of this data in her opinion are that accrual was <20% of what was planned, 40% of patients were not treated at first progression, the study was underpowered to show meaningful differences, and patients were not well-balanced between the groups (the abiraterone/enzalutamide group had more liver metastases, high PSA, and higher LDH).
Further questions/conclusions from this study were:
- Do clinical determinants of aggressive disease recommend early germ-line and somatic genomic analysis from a liquid or tissue biopsy?
- Do high ctDNA/ctDNA fraction, AR-V7, RB and/or p53 alteration provide grounds for considering chemotherapy or clinical trial?
- When there are unfavorable clinical parameters and genomics, it is important to set patient expectations regarding low/short response rates with standard therapy
- If there are alterations in DNA repair genes (especially BRCA1/2), consider PARP inhibitor trial or standard of care plus PARP inhibitor
Dr. Taplin congratulates the authors for doing this trial and concluding that we can avoid a potential toxic medication (metformin, 70% grade 1-2 gastrointestinal adverse effects), commonly prescribed off label. The main challenges of this study were the PSA endpoint and relatively small sample size.
Presented by: Mary-Ellen Taplin, MD, Dana-Farber Cancer Institute, Boston, MA
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA
- Francini E, Gray KP, Shaw GK, et al. Impact of new systemic therapies on overall survival of patients with metastatic castration-resistant prostate cancer in a hospital-based registry. Prostate Cancer Prostatic Dis 2019 Jan 14 [Epub ahead of print].