Showing posts with label PARP inhibitor. Show all posts
Showing posts with label PARP inhibitor. Show all posts

Tuesday, October 1, 2019

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.
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.

Triton 3 (comparing rucaparib to abiraterone, enzalutamide or docetaxel) is ongoing.

(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).

Thursday, February 1, 2018

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.

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:

Carboplatin trials specifically for men with DNA-repair defects:

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.