ASCO 2022: Discussant: AR and PARP: Partners in Crime

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a discussant presentation by Dr. Heather Cheng discussing important abstracts incorporating inhibition of AR + PARP in advanced prostate cancer. Dr. Cheng discussed the following abstracts “BRCAAway: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with mCRPC with DNA repair defects” presented by Dr. Maha Hussain, “Tolerability of abiraterone combined with olaparib in patients with mCRPC: Further results from the phase III PROpel trial” presented by Dr. Antoine Thiery-Vuillemin, and “Gene-by-gene analysis in the MAGNITUDE study of niraparib with abiraterone acetate and prednisone in patients with mCRPC and HRR gene alterations” presented by Shahneen Sandhu.


By way of background, Dr. Cheng notes that ~25% of mCRPC harbor inactivating changes in genes important to homologous recombination repair (HRR). Patients with mCRPC associated with such mutations (somatic or germline) are candidates for precision therapy, such as PARP inhibitor and platinum chemotherapy. Olaparib and rucaparib are FDA approved for more than two lines of therapy in mCRPC with mutations in BRCA2, BRCA1, and other HRR genes. Niraparib, talazoparib, plus other agents are also actively being studied.

Dr. Cheng notes that there are several open questions in this disease space:

  • Does combined inhibition of AR + PARP inhibitors result in therapeutic synergy?
  • Is biomarker positivity necessary or sufficient to observe benefit?
  • Is combined inhibition of AR + PARP feasible and tolerable?
  • Can we further refine predictive biomarkers in this context?

BRCAAway is a randomized phase 2 trial in which mCRPC patients underwent tumor next generation sequencing and germline testing. Patients with inactivating BRCA1, BRCA2 and/or ATM alterations were randomized 1:1:1 to Arm 1 abiraterone (1000 mg daily) + prednisone (5mg bid) (abiraterone + prednisone), Arm 2 olaparib (300 mg bid) or Arm 3 olaparib + abiraterone + prednisone. The primary endpoint is progression-free survival (PFS), and secondary endpoints include measurable disease response rate by RECIST, PSA-RR, undetectable PSA (≤ 0.2 ng/ml), and toxicity. The trial schema for BRCAAway is as follows:

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Dr. Cheng notes that the crossover design of this trial allows comparison of combination versus sequential single agents. The gene alteration composition included BRCA2 (75%), ATM (20%), and BRCA1 (5%). ≥50% PSA decline was reported in 79% of patients in Arm 1, 81% in Arm 2, and 90% in Arm 3. Median PSA nadir for Arms 1 was 2.17 ng/mL (95% CI 0.40, 49.27), for Arm 2 was 3.10 ng/mL (95% CI 0.83, 5.00), and for Arm 3 was 0.60 ng/mL (95% CI 0.10, 1.97), respectively. Undetectable PSA, median PFS, and 12-month PFS by Arm are listed as follows:

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The Kaplan Meier curves for time to first progression by study arm is as follows:

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Dr. Cheng notes several summary points from the BRCAAway trial:

  • This study provides further data supporting synergy of combine inhibition of AR + PARP (75% BRCA2)
  • This study provides unique comparison of combination versus sequence of single agents
  • Longer follow-up and more data is anticipated

As follows is a summary of the BRCAAway, PROpel, and MAGNITUDE studies, highlighting each trial’s eligibility, biomarker considerations, treatment, and rPFS outcomes:

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Dr. Cheng then discussed updated safety data from the PROpel trial. The main take-away points from this analysis are as follows:

  • The COVID-19 pandemic was considered not to have had a meaningful impact on the study, including the interpretation of the results
  • There was no imbalance between the treatment arms for cardiac failure or arterial thromboembolic events
  • Anemia was managed primarily by dose modifications
  • The most common venous thromboembolic event was pulmonary embolism. In both arms, most findings were incidental or asymptomatic

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Dr. Cheng notes that 16% of patients had >=1 blood transfusion, which is burdensome for patients, given that 1-2 units of red blood cells can take 8-12 hours to infuse. Furthermore, although most venous thromboembolisms were incidental/asymptomatic, management is also burdensome given that anticoagulation is daily or BID injection or oral medication. Taken together, patient-centered considerations include time off of work, cost of medications, drug-drug interactions, higher bleeding risks, and greater treatment complexity. Dr. Cheng’s summary for this study is that (i) the combination of abiraterone + olaparib is tolerable, (ii) anemia and venous thromboembolism rates are ~5-15% and can be managed, however (iii) management comes with added patient burden.

The third study discussed by Dr. Cheng was the gene-by-gene analysis of the MAGNITUDE study. This was a pre-specified analysis was undertaken of the primary endpoint (radiographic progression-free survival [rPFS] by BICR), secondary endpoints (time to cytotoxic chemotherapy, time to symptomatic progression, overall survival), as well as time to PSA progression and overall response rate across 186 patients (91 randomized to niraparib + abiraterone acetate + prednisone, and 95 to placebo + abiraterone acetate + prednisone) with an alteration in the ATMBRIP1CDK12CHEK2FANCAHDAC2, or PALB2 gene (excluding co-occurring alterations). This analysis of individual alterations was not powered for formal statistical inference. Given the rarity of some alterations, groups based on functional similarity (HRR-Fanconi group [BRIP1, FANCE, PALB2] and HRR-associated group [CHEK2, HDAC2]) are also presented. Different proteins can detect double-strand breaks, such as the FANC complex, which recruit HRR effectors including BRCA1, BRCA2, and PALB2. The trial schema for this trial and the analysis is as follows:

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Dr. Cheng notes that for PALB2, CHEK2, and HDAC2, each of these mutations showed benefits across all clinical endpoints. For CKD12, there was no benefit in the primary or >1 secondary endpoint, and for ATM there was a mixed bag for clinical efficacy:

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Dr. Cheng concluded her presentation by discussing AR + PARP inhibitor combination therapy with the following concluding points:

  • Does combined inhibition of AR + PARP result in therapeutic synergy? Yes, but context matters, and degree of synergy depends:
    • Yes, likely in the BRCA2 mutated, and for other mutations data is emerging
    • By HRR mutation + versus HRR negative?
    • By difference in methods of biomarker assignment?
    • By effects of variable ARSI exposure?
  • Is biomarker positivity necessary or sufficient to observe a benefit? Not clear as of yet
  • Is combined inhibition of AR + PARP feasible and tolerable? Yes, but there is some burden on patients
  • Can we further refine predictive biomarkers in this context? Yes, but we must work together

Finally, Dr. Cheng added the following parting thoughts:

  • There is strong evidence that inhibition of AR and PARP can be synergistic, but more comprehensive characterization needed to define the contexts of greatest success and the contexts where we can do better
  • The potential benefits are real, but the management of toxicities has hidden burdens. This is important as we strive to increase diversity of our clinical trial populations to better represent the spectrum of patients in our communities
  • More follow-up data for these and other studies are coming. Additionally, how will other combinations (ie. Enzalutamide + PARP inhibitors, Lu177 + PARP inhibitors) compare?

Presented by: Heather H. Cheng, MD, PhD, University of Washington, Seattle, WA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022. 

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