ASCO 2019: Aggressive Therapy for Aggressive Disease

Chicago, IL ( Mary-Ellen Taplin, MD, from the Dana-Farber Cancer Institute provided a discussion of Abstract 5003 “Updated results from a randomized phase II study of cabazitaxel (CAB) versus abiraterone (ABI) or enzalutamide (ENZ) in poor prognosis metastatic CRPC”, Abstract 5004 “TAXOMET: A French prospective multicenter randomized controlled phase II study comparing docetaxel plus metformin versus docetaxel plus placebo in mCRPC” and Abstract 5005 “TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations” at ASCO 2019

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
Several challenges:
  • Timing of molecular testing
  • Availability of liquid or tissue material
  • Tumor heterogeneity
  • Lack of drugs for most tumor drivers
  • Resistance
  • Data sharing
  • 85% of cancer care is delivered in the community setting
So, who do we treat with what and when? There are several current prostate cancer predictive biomarkers, including (i) homologous recombination deficiency – selecting for PARP inhibitors, platinum chemotherapy; (ii) aggressive/poor prognosis mCRPC – include patients with visceral metastasis, low PSA, adverse genomics (ie. p53, Rb mutations); (iii) AR-V7 and imaging.

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
The TAXOMET study was a phase II prospective multicenter randomized controlled trial testing docetaxel plus prednisone and either metformin (arm A) or placebo (arm B), for up to 10 cycles among 99 men with mCRPC. The primary endpoint was PSA response rate (≥50% decrease). Main secondary endpoints included objective response rate (ORR, according to RECIST v1.1), clinical and biological progression-free survival (PFS), overall survival (OS), toxicity and quality of life (QoL). Over a median follow-up of 41.1 months (range 38.5-54.1), there was no difference observed between arm A and arm B in PSA-response rate (arm A 66%, arm B 63%; p=0.94), ORR (28% in both arms), clinical or biological mPFS (7.4 months vs 5.6 months p = 0.848) and median OS (24.6 months vs 19.7 months, p = 0.53), respectively.

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

  1. 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].