Abiraterone/enzalutamide+PARP inhibitor better than abiraterone/enzalutamide alone for mCRPC

(updated)

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
• In an update, overall survival has increased to 42.1 mos. for the combination from 34.7 mos. with abi only - an improvement of 19%.
• The improvement was greater in those with the DNA mutations (+34%) than in those without such mutations (+11%); the benefit was +71% in those who were BRCA+
• Time to next therapy and time to next progression were also lengthened
• QOL was not diminished by the combination vs the montherapy, although the usual adverse events associated with PARP inhibitors were observed (hematological side effects and fatigue mostly).

The FDA approved the combination, but only for patients with BRCA+ mutations.

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

(update 9/14/23) An update with overall survival (OS) was reported after 36.5 months of follow-up.

• Mortality was 19% lower for olaparib than the placebo which was not statistically significant. 
• Median OS was 42 months for olaparib vs 35 months for the placebo, but the difference was not quite statistically significant.
• Those with HRR mutations were 34% less likely to die, which was statistically significant.
• Those without HRR mutations were 11% less likely to die, which was not statistically significant.
• There was no difference for the first 2 years of follow-up, but then the group taking olaparib did better.
• The greatest benefit for the combination was in patients who had germline HRR mutations, and in patients who had BRCA+ mutations specifically.
• Among those taking olaparib, 40% suffered a serious adverse events, particularly anemia (50% all-grade, 16% grade 3+).
• Almost half of patients taking olaparib interrupted treatment due to an adverse event.

The TALAPRO-2 clinical trial randomized 1,037 mCRPC patients independent of their DNA-damage repair (DDR) defect status to one of 2 groups:

• Talazoparib + enzalutamide +ADT ("tal-combo")
• Placebo+enzalutamide+ADT ("enza")

In the first report:

• radiographic progression-free survival (rPFS) increased by 37% for the tal-combo over enza alone
• +54% among those with a DDR mutation
• +30% among those without a DDR mutation
• Improvements in any tumor response (61.7% vs 43.9%)
• Improvements in complete tumor response (37.5% vs 18.2%)
• 28% improvement in time to PSA progression
• 51% improvement in time to chemotherapy
• 22% improvement in time to QOL deterioration
• Overall survival data is not yet mature (<50% have died in the enza group)

Side effects (mainly hematological) were significant:

• ⅔ experienced anemia, for which 43% of tal-combo patients had to have a transfusion
• Grade 3 or 4 (serious or life-threatening) adverse events occurred in 72% of the tal-combo group vs 41% of the enza group.

• Other than hematological adverse effects, 34% experienced fatigue (vs 29% for enza), 22% experienced back pain (vs 18% for enza), 22% had decreased appetite (vs 16% for enza), and 21% had nausea (vs 12.5% for enza).
• About 80% of patients were able to complete the tal-combo at full dose

Talapro-3 will determine if there is any benefit to earlier treatment - while men are still hormone-sensitive and have at least one DDR mutation.

The MAGNITUDE clinical trial randomized 423 mCRPC patients with (Arm 1)DNA repair defects and (Arm 2) 233 without DNA repair defects to: 

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

After 19 months of follow-up, Arm 2, the group that did not have DNA repair defects was stopped for futility because there was no benefit in rPFS in that group.

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 niraparib 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 suggests there may be a benefit (sample size is low) in men with defects in CHEK2.

In an update presented at ASCO, Eleni Efstathiou presented the following (note: benefits were always improved in the BRCA+ subgroup):

• rPFS was 16.7 mos with nira+abi vs 13.7 mos. with placebo+abi
• Time to symptomatic progression was lengthened by 40%
• Time to chemotherapy was lengthened by 33%
• Overall survival was unchanged, but the data is immature (too few people have died)

(Update 7/4/23) A second interim analysis at 24.8 months median follow-up showed:

• rPFS was 19.5 mos with nira+abi vs 10.9 mos. with placebo+abi
• Time to symptomatic progression was lengthened
• Time to chemotherapy was lengthened 
• Overall survival improved by 46% compared to those who did not initiate PARP inhibitors at any subsequent time. 

Eleni Efstathiou, the lead investigator of the MAGNITUDE trial, believes that the trial design explains why men without DNA repair defects benefited from the PARP inhibitor in the PROpel and TALAPRO-2 trials, but not in the MAGNITUDE trial. She believes that the subgroup that was stopped early might have shown some benefit if they had continued. I can also 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. 

(update 4/28/23) The FDA has decided to only approve the combination for patients who are BRCA+

Limited FDA approval

(update 1/26/24) The BRCAAway trial randomized 61 BRCA+ and ATM+ mCRPC men to:

1. abiraterone
2. olaparib
3. abiraterone+olaparib

In addition, men in Group 1 and 2 were allowed to cross over to the other medicine upon progression.

The results were:

• Progression-free survival (PFS) was 8 months for abi, 14 months for olaparib, and 39 months for the combination.
• Objective Response Rate (ORR) was 22% for abi, 14% for olaparib, and 33% for the combination
• % of patients with PSA reduction of more than 50% (PSA50) was 61% for abi, 67% for olaparib, and 95% for the combination
• Undetectable PSA was 17% for abi, 14% for olaparib, and 33% for the combination
• Although patients responded to cross-over, it was never as good as starting with the combination
• Adverse events were as expected for each medication