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

PARP inhibitors slow progression and increases survival in men with BRCA gene mutations

The PROfound Trial has reported (here) significant improvements in progression-free survival in men with BRCA2, BRCA1, and ATM gene mutations who took the PARP inhibitor, olaparib (Lynparza). BRCA2, BRCA1, and ATM germline gene mutations are found in about 8% of men with metastatic castration-resistant prostate cancer (mCRPC). The study also included men in whom those genes were mutated in their tumors (called "somatic" mutations). PARP inhibitors inhibit an enzyme that supports the survival of DNA-damaged cancer cells. Lynparza is FDA-approved for ovarian cancer and breast cancer. Other FDA-approved PARP inhibitors comprise Rubraca (rucaparib) and Zejula (niraparib) for ovarian cancer, and Talzena (talaparib) for breast cancer. They are all in clinical trials for prostate cancer (see this link).

The PROfound Trial (details here) compared the effectiveness of Lynparza to either Xtandi or Zytiga (cohort B) in men who had already failed one of them. They compared the two groups in men who had somatic mutations in BRCA 1/2 or ATM (Cohort A, n=245) and in men who had somatic mutations in any of 12 other DNA-repair genes (Cohort B, n=142), and in men who had any of the 15 DNA-repair mutations (Cohort A+B, n=387). The trial was conducted at 229 sites. The 12 other DNA-repair mutated genes were BARD1, BRIP1, CDK12, CHK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, and RAD54L.

Their interim (median 1 year) findings comparing Lynparza vs Xtandi/Zytiga were as follows:

Median radiographic progression-free survival (rPFS):

• Cohort A: 7.4 months vs 3.6 months (HR=0.34, p<0.0001)
• Cohort A+B: 5.8 months vs 3.5 months (HR=0.49, p<0.0001)

Among the combined cohorts (A+B):

• 6-month rPFS: 60% vs 23%
• 12-month rPFS: 28% vs 9%
• Objective Response Rate: 33% vs 2%
• Time to pain progression: not reached vs 10 months

Median overall survival (OS) (updated 9/22/20 ):

• Cohort A: 19.1 months vs 14.7 months (HR=0.69, p=0.02)
• Cohort A+B: 17.3 months vs 14.0 months (not statistically significant)
• Cohort B: 14.1 months vs 11.5 months (not statistically significant)
• Two-thirds of controls crossed-over to receive olaparib
• After adjusting for cross-over, the hazard ratio improved to 0.42 in Cohort A, but were not significant in Cohort B or Cohort A+B

Adverse Events:

• Lynparza patients had more anemia, nausea, fatigue & asthenia, decreased appetite, diarrhea/constipation, vomiting, and respiratory issues.
• 16.4% discontinued with Lynparza vs 8.5% discontinued with hormonal therapy
• Nevertheless, they stuck with Lynparza for 7.4 months  vs 3.9 months with hormonal therapy

(update 5/19/20) The FDA approved Lynparza for mCRPC patients with germline or somatic homologous recombination repair mutations who have progressed on Zytiga or Xtandi.

In a small study (12 BRCA1/2-mutant, 5 ATM-mutant), Marshall et al. reported activity in men with BRCA1/2 mutations, but not ATM mutations:

• Reduction of PSA by at least 50% was seen in 83% of men with BRCA1/2 mutations vs 0% of men with ATM mutations.
• Progression-free survival was 12.3 months in men with BRCA1/2 mutations vs 3.3 months in men with ATM mutations.

Similarly good responses among men with bi-allelic (both genes mutated) BRCA1/2 mutations vs other DNA-repair mutations were reported in a Phase 2 trial of niraparib. The FDA has granted it "breakthrough therapy" designation.

Men with CDK12 mutations (one of the DNA repair mutations in Cohort B of the PROfound trial) unsurprisingly did not respond to PARP inhibitors (see this link).

Preliminary results of the TRITON 2 clinical trial of rucaparib in men with DNA-damage repair (DDR) deficiencies (either germline or somatic) were also reported. Clinical benefit (the % who had no radiographic progression and stayed with rucaparib) at 6 months and 12 months for each of the DDR genes found were as follows:

• BRCA1/2: 56% (47/84) at 6 mos., 25% (6/53) at 12 mos.
• ATM: 29% (14/48) at 6 mos., 8% (2/25) at 12 mos.
• CDK12: 21% (3/14) at 6 mos., 7% (1/14) at 12 mos.
• CHK2: 67% (2/3) at 6 mos., 0% (0/1) at 12 mos.
• Other DDR: 50% (6/12) at 6 mos., 33% (3/9) at 12 mos.

(update 8/23) The percent who had a reduction in PSA greater than 50%:

• BRCA1/2: 53%
• PALPB2: 55%
• ATM: 3.4%
• CDK1/2: 6.7%
• CHEK2: 14%
• Other DDR: 23%

There was high treatment-related toxicity in these heavily pre-treated patients:

• Treatment interruption or dose reduction in 54%
• Discontinuation in 9.5%
• Most common serious (grade 3+) adverse events: anemia (18%), fatigue (11%), thrombocytopenia (6%)
• 5 deaths (3%)

(Update 5/15/20) The FDA approved rucaparib for men who have the BRCA mutation (either germline or somatic, and have had prior taxane chemotherapy and AR-directed hormone therapy.

(Update 2/18/23) Triton 3  compared rucaparib to physician's choice of abiraterone, enzalutamide or docetaxel in 405 patients who were either BRCA+ or ATM+. After 62 months of follow-up:

• radiographic Progression Free Survival (rPFS) was 10.2 mos. vs 6.4 mos. -- 39% improvement for rucaparib.
• rPFS was 11.2 mos. vs 6.4 months in those who were BRCA+ (50% improvement)
• rPFS was not significantly different for ATM+ patients
• (update) rPFS improvement was 36% compared to docetaxel, and 53% compared to abi or enza
• In those with BRCA+, rPFS improvement was 47% compared to docetaxel, and 62% compared to abi or enza
• fatigue, nausea, and high BP were the most non-hematological frequent adverse events
• anemia and neutropenia were the most serious hematological events

(Update 2/22/21) Early results of the TALAPRO-1 trial of talaparib have been presented. The 128 patients were previously treated with docetaxel, and half had cabazitaxel too. The trial only included patients with genomic DNA damage-repair (DDR) defects.

• The overall objective response rate (ORR) was 30% 
• 46-50% for BRCA1/2
• 25% for PALB2
• 12% for ATM
• ORR took 3.4 months to be observable and lasted for 12.8 months
• Radiographic progression-free survival (rPFS) was 5.6 months
• 11.2 months for BRCA1/2
• 5.6 months for PALB2
• 3.5 months for ATM and other DDR defects
• Most saw a reduction in tumor burden (82%), PSA (72%), and CTC (82%)
• Reductions greatest BRCA1/2>PALB2>ATM (similar patterns in overall survival and time to PSA progression).
• The most common treatment-emergent adverse events were anemia (49%), nausea (33%), decreased appetite (28%) and asthenia (24%).
• Serious/life-threatening adverse events included anemia (31%), decreased platelet count (9%), neutropenia (8%), and pulmonary embolism (6%)
• 12% discontinued treatment due to adverse events

Patients are encouraged to get the relatively inexpensive ($249) germline test, or if negative for actionable mutations, a genomic test of a tumor biopsy or of cell-free DNA (from a blood test).

Inexpensive screening for germline mutations to personalize treatment

Pritchard et al. last year discovered that certain rare germline mutations that interfere with DNA-repair mechanisms occur with greater than expected frequency in men with aggressive prostate cancer. A "germline mutation" means that it is inherited from one's parents and is part of a man's normal genetic profile, for better or worse. By contrast, a "somatic mutation" means that it occurs only in tumor tissue and not necessarily in normal cells. There are several genes responsible for repair of our DNA. Their job is to fix random replicative errors as they crop up, and to cause cells that cannot be repaired to commit suicide (apoptosis) before they can become cancerous. When our inherited germline DNA repair genes are faulty, cancers may appear at any time and grow unchecked. They also can result in radio-toxicity because healthy cells can't fix the X-ray damage to their DNA and die off en masse. This is the case for ATM and ATR mutations that occur in both copies of the inherited genes (called "bi-allelic") When tumor DNA repair is faulty, as it often is, the cells become immortal, DNA errors proliferate and lead to such phenomena as EMT (cells able to exist outside of the prostate and migrate easily), castration resistance, and drug resistance.

The table below shows the incidence of several of the most important DNA-repair genes and their prevalence (1) in men with metastatic prostate cancer (2) in men with localized prostate cancer, and (3) in men in the general population who don't have prostate cancer. About 1 in 8 (12%) men who have detected metastases have a germline DNA repair defect. That falls to only about 1 in 22 men who have localized prostate cancer, and 1 in 37 men without prostate cancer.

It is only worth knowing about if there is something we can do about it. Someday we may have gene editing tools that can correct those aberrations throughout the body. CRISPR and Zinc Finger technology are in their infancy, and have only just started to be used in clinical studies for prostate cancer. The two medicines we have in our armamentarium against prostate cancer in those with germline DNA-repair defects are PARP inhibitors (e.g., olaparib, rucaparib, talazoparib, etc.) and platinum-based chemotherapy (e.g., carboplatin, oxaliplatin, etc.). (Update Oct. 2019) Recent trials suggest that only those with the BRCA1/2 mutations (and maybe CHK2) respond to current PARP inhibitors see this link).

Color Genomics

Color Genomics is a division of Genome Dx, the same company that offers the Decipher test. They are now offering a 30-gene panel listing the most frequently observed mutations in DNA-repair genes. It includes all of the genes listed in the table above plus other genes that have been implicated in other cancers (see the list here). They also look for aberrant TP53 and PTEN - two gene mutations that have been implicated in the loss of tumor suppression and loss of apoptosis, and are prognostic for aggressive prostate cancer variants. What is astounding is the price -- only $249! A full genomic analysis of BRCA2 would cost somewhere between $2,000 to $3,000. By limiting  their analysis to the most common site mutations, they are able to make it affordable, albeit not as thorough. It can be ordered by a physician (they will provide one if necessary). It is a simple saliva test that the patient mails in, and genetic counseling is included with the results.

(Update) The Color Genomics test is available free of cost to men who have a diagnosis of prostate cancer - they are building a registry database.  Interested patients can obtain it by putting their contact info in the website below. They mail a saliva test kit and pay for the return postage.

https://www.prostatecancerpromise.org/

Associated with other indicators of poor prognosis

A team at Johns Hopkins reported on their use of the Color Genomics test in 150 patients to determine whether germline DNA-repair defects were associated with two rare and aggressive prostate cancer variants: ductal and intraductal prostate cancer. They also looked for associations with lymphovascular invasion discovered at pathology. Velho et al. reported:

• Ductal/intraductal histology was discovered in 48% who had the defects vs only 12% who were free of those defects.
• Lymphovascular invasion was discovered in 52% who had the defects vs. only 14% who were free of those defects.
• 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines. (update note: NCCN has changed its guidelines)

Other tests

While 23andMe offers a germline test that the consumer can order without a doctor, it is inferior. There are, say, 10,000 or more genetic mutations that can occur within a single BRCA2 gene. 23andMe only looks at a narrow pre-defined range of genomic abnormalities, using a silicon SNP array. Color Genomics uses "next generation sequencing" to look at many more types of genomic aberrations. There are other tests available from AmbryGenetics and Myriad.

Those who test positive may wish to investigate a clinical trial of a PARP inhibitor:

• Olaparib (multiple US & Int'l locations)
• Niraparib + Zytiga vs Zytiga alone for mCRPC -multiple locations
• Olaparib + Keytruda (cohort A) mCRPC- multiple locations
• Olaparib + durvalumab recurrent - Memorial Sloan Kettering
• Olaparib + abiraterone - multiple sites
• Olaparib+ AZD6738 (ATR inhibitor) - U Mich
• Rucaparib (Phase 2) mCRPC - multiple sites
• Rucaparib +abiraterone or enzalutamide - sites TBD
• Rucaparib vs Zytiga/Xtandi/Taxotere(Phase 3) mCRPC - multiple sites
• Niraparib mCRPC - multiple sites
• Bavencio (PD-L1 inhibitor) + Talazoparib -mCRPC -multiple sites
• BGB-290 + Temozolomide - locally advanced/metastatic - multiple sites
• Olaparib + Xofigo -mCRPC - UCSD & Ohio State U
• Olaparib - recurrent - Baltimore, Omaha, Phila & Pittsburgh
• Jevtana, carboplatin then olaparib - aggressive variants - MD Anderson
• Talazoparib + Zytiga/Xtandi - mCRPC - multiple locations
• Talazoparib + Avelumab -locally advanced/metastatic - NY & AZ
• Talazoparib - mCRPC - multiple locations
• Rucaparib -mHSPC & ADT-naive- Johns Hopkins
• Rucaparib + carboplatin + docetaxel - mCRPC (allows somatic mutations)- UWashington Seattle
• Rucaparib - germline or somatic- UOP

Carboplatin trials specifically for men with DNA-repair defects:

• Docetaxel + Carboplatin - mCRPC - VA Hospitals, LA & Puget Sound
• Docetaxel + Carboplatin - mCRPC - UWashington Seattle
• Carboplatin - mCRPC - Zurich
• Carboplatin - mCRPC - UK

Most (7 out of 8) metastatic patients will learn nothing from this test and it will be a waste of money. But for some who seem to have an unusually aggressive prostate cancer variant, have ductal/intraductal histology, or have had lymphovascular invasion identified at pathology, it may be worth paying for the relatively inexpensive test. It may indicate that a platin may be a preferred form of chemo, or that a clinical trial of a PARP inhibitor may be warranted.