Barcelona, Spain ( Dr. Elena Castro discussed four important studies regarding PARP inhibitors presented at European Society for Medical Oncology (ESMO) 2019’s annual congress Prostate Cancer Session.

These included:

I. GALAHAD: (NCT02854436):A Phase II study assessing niraparib (300 mg daily) in patients with metastatic castration-resistant prostate cancer (mCRPC) and DNA repair defects (n=81) with disease progression on taxane and androgen receptor-targeted therapy. In BRCA patients, overall response rate (ORR) was 41% and complete remission rate (CRR) was 63%, with a median duration of objective response of 5.5  month (range: 3.5–9.2 months). Median radiographic progression-free survival (rPFS) and overall survival (OS) in BRCA patients were 8.2 and 12.6 months, respectively. In non-BRCA, objective response was noted in only 9% of patients and CRR was 17%, with durations of objective response of 3.8 and 6.5 months, respectively. The median rPFS for non-BRCA patients was 5.3 months and OS was 14.0 months. Among BRCA patients, 50% had a ≥ 50% decline in prostate-specific androgen (PSA), compared to 3% of non-BRCA patients.

II. Multicenter analysis of cyclin-dependent kinase 12 (CDK12) mCRPC patients (n=58): Of those undergoing primary ADT (n = 54), only 85% had a PSA50 response, with a median PFS of 11.8 (95% CI 8.3–15.4) months. Of those receiving first-line abiraterone or enzalutamide for mCRPC (n = 34), only 47% had a PSA50 response, with median PFS of 4.3 (95% CI 2.6–6.0) months. Of those receiving a taxane agent first for mCRPC (n = 20), only 35% had a PSA50 response, with median PFS of 4.0 (95% CI 2.6–5.3) months. Eleven men received a poly ADP-ribose polymerase (PARP) inhibitor, of which none had a PSA50 response, and median PFS was only 3.6 (95% CI 3.0–4.2) months. Eight men received a PD1 inhibitor, of which 38% had a PSA50 response, and median PFS was 6.6 (95% CI 2.3–10.8) months.

III. TRITON2: (NCT02952534) A Phase II study evaluating rucaparib 600 mg twice daily in patients with mCRPC (n=190) and a deleterious germline or somatic alteration in BRCA1, BRCA2, ATM, CDK12, or other prespecified DNA damage responsive (DDR) gene. Among the patients with a BRCA mutation and measurable disease at baseline, 43.9% had a confirmed ORR, and responses were durable with the majority lasting >24 weeks. 52.0% of BRCA mutation patients had a confirmed PSA response (>50% decrease), with a median duration of PSA response of 5.5 months.

IV. PROfound (NCT02987543) detection of homologous recombination repair gene mutations: A qualifying homologous recombination repair gene mutation was observed in 27.9% of mCRPC patients with a successful tumor test result, most commonly BRCA2 (8.2)%. A co-occurring qualifying homologous recombination repair gene alteration in ≥ 1 gene was detected in 59 (7.6%) patients, most commonly BRCA2.

Dr. Castro notes that different alterations confer different degrees of DNA repair impairment, likely resulting in different sensitivity to PARP inhibitor synthetic lethality. This meeting highlights the reporting of three important Phase II/III trials utilizing PARP inhibitors:

phase III trials 1
phase III trials 2

Dr. Castro notes that in the PROfound study, the tissue test failure rate was 31% and that sequencing success rates were higher for samples from metastases (75%) than for prostate tumor tissue (68%). The most common reason for screening failure was at the DNA extraction step (42% of failures), followed by post-DNA extraction failure (22.3%), and pathology (22.1%). Further work increasing the yield of patients with available gene data is paramount.

Comparing TRITON2 and GALAHAD, Dr. Castro notes that both had similar objective response rates: 41% in GALAHAD vs 43.9% in TRITON2. Similarly, both trials had ~50% confirmed PSA response rate (GALAHAD 50%, TRITON2 52%). Among patients with BRCA1/2 mutations, 60% of patients in TRITON2 had a radiographic durable response ≥6 months, while median duration of objective response in GALAHAD was 5.6 months. Objective and PSA response rates in patients with other DNA repair deletion alterations was poor in both studies: 14.6% confirmed ORR in TRITON2 vs 9% in GALAHAD; 9.8% confirmed PSA response in TRITON2 vs 3% in GALAHAD. To summarize, both niraparib and rucaparib work well in BRCA mutations and generally quite poorly in the other DDR mutations.

One particularly resistant gene mutation to PARP inhibitors is CDK12, noted to be present in 1.2% of patients screened for in the PROfound study. Dr. Castro notes that CDK12 biallelic loss delineates a distinct immunogenic class of advanced prostate cancer. Based on the data from Dr. Antonarakis’ study, these are young men (median 60 years at diagnosis), with aggressive disease (79% Gleason Grade 5), with 47% having metastasis at diagnosis. However, perhaps there is hope that these patients may do marginally better with checkpoint inhibitor therapy, with 38% having a PSA50 response, with a median PFS of 6.6 (95% CI 2.3–10.8) months.

Dr. Castro concluded her summary discussion of these PARP inhibitor studies with the following take-home points:

  • PARP inhibitors rucaparib and niraparib have high and durable clinical activity in mCRPC patients with some DDR defects after progression on various lines of therapies. However, response rates are higher in patients with BRCA1/2 mutations. She notes that predictors of response beyond identification of a BRCA defect are needed
  • The findings support the implementation of tumor/plasma testing in routine clinical practice for advanced prostate cancer
  • Further developments in testing are needed for the analysis of some samples and sampling outside of academic centers is strongly encouraged

Presented by: Elena Castro, MD, PhD, Hospital Virgen de la Victoria, Prostate Cancer Clinical Unit, Spanish National Cancer Research Center, Madrid, Spain

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept – 1 Oct, 2019 in Barcelona, Spain