Friday, June 3, 2022

Abiraterone+PARP inhibitor better than abiraterone alone for mCRPC

PARP inhibitors have been approved for men with metastatic castration-resistant prostate cancer (mCRPC) who have certain defects in their DNA-repair mechanism, mainly defects in their BRCA genes. So far, two PARP inhibitors have been approved: olaparib (Lynparza) after progression on abiraterone (Zytiga) or enzalutamide (Xtandi), and rucaparib (Rubraca) after a second-line hormonal medicine and docetaxel. Two other PARP inhibitors, niraparib (Zejula) and talazoparib (Talzenna) are not yet approved. (See this link). PARP inhibitors prevent cancer cells from fixing DNA mistakes that are more prevalent when one already has the defective BRCA gene.

Hypothetically, PARP inhibitors can delay progression in cancer cells whose DNA is already being disrupted by radiation: Xofigo or Pluvicto. Lynparza has been found to have no benefit when used with Keytruda. A trial of bipolar androgen therapy (BAT) with Lynparza found that the combination delayed progression considerably in men without DNA-damage repair defects. They may also be useful when cell replication is being slowed by docetaxel+carboplatin or second-line hormonals, even in men who do not have DNA damage repair defects. Enzalutamide may be able to prevent cross resistance between docetaxel and PARP inhibitors (see this link)

The PROpel clinical trial randomized 796 mCRPC patients in 17 countries to get either:

  • abiraterone + olaparib, or
  • abiraterone + placebo
  • a quarter had already had docetaxel
  • none were previously treated with a second-line hormonal
  • all were tested (Foundation One) for DNA damage defects which were found in ~28% of patients

With about 21 months of follow-up, radiographic (any kind of imaging) progression-free survival (rPFS) was:

  • 25 months in the olaparib group vs 17 months without olaparib (HR=0.66)
  • Benefit did not differ significantly by type of metastasis, previous docetaxel, or whether they had pre-existing DNA damage repair defects

Follow-up was not long enough to detect significant differences in overall survival, but other secondary endpoints showed benefit for the combination:

  • PSA response was 79% with olaparib vs 69% without it
  • Time to PSA progression was not reached for olaparib vs 12 months without it
  • Tumors shrank in 58% with olaparib vs 48% without it
  • Time to next therapy was reduced by 26% due to olaparib
  • Time before progression on the next therapy was reduced by 31% due to the olaparib therapy

Some adverse events were markedly increased among those taking olaparib:

  • any grade 3 was reported by 47% with olaparib vs 38% without it
  • interruption of the drug among 45% taking olaparib (33% interrupted abiraterone) vs 25% taking placebo (22% interrupted abiraterone)
  • dose reduction of the drug among 20% taking olaparib vs 6% taking placebo
  • discontinuation of the drug among 14% taking olaparib vs 8% taking placebo
  • anemia  among 46% (15% grade 3) taking olaparib vs 16% (3% grade 3) taking placebo
  • fatigue among 37% taking olaparib vs 28% taking placebo
  • nausea among 28% taking olaparib vs 13% taking placebo
  • diarrhea among 17% taking olaparib vs 9% taking placebo
  • decreased appetite among 15% taking olaparib vs 6% taking placebo
  • pulmonary embolism among 7% taking olaparib vs 2% taking placebo

The MAGNITUDE clinical trial randomized 423 mCRPC patients with DNA repair defects and 233 without DNA repair defects to: 

  • abiraterone + niraparib, or
  • abiraterone + placebo
  • 23% had prior abiraterone

After 19 months of follow-up:

  • There was no benefit in rPFS among those lacking DNA repair defects

Among those with DNA repair defects:

  • rPFS was 17 months with niraparib vs. 14 months with placebo
  • if they had BRCA defects, rPFS was 17 months with niraparib vs 11 months with placebo
  • time to chemotherapy was increased by 41% by niraparib
  • time to symptomatic progression was increased by 31% by niraparib
  • time to PSA progression was increased by 43% by niraparib
  • tumors more than doubled without olaparib vs with nirparib
  • discontinuation of the drug among 9% taking niraparib vs 3.8% taking placebo
  • Grade 3+ adverse events occurred in 67% taking niraparib vs 46% taking placebo
A more granular analysis of specific DNA repair genes suggest there may be a benefit (sample size is low) in men with defects in:
  • ATM
  • PALB2
  • CHEK2
  • CDK12
I don't know why men without DNA repair defects benefited from the PARP inhibitor in the PROpel trial and not in the Magnitude trial. I can conjecture that:
  • Olaparib is a stronger PARP inhibitor (based on worse side effects)
  • The olaparib group was less progressed
  • The previous docetaxel use by ¼ in the olaparib trial sensitized the cancer, whereas the previous abiraterone use in the niraparib trial had no sensitization effect. 













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