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October 1, 2019.  A study presented yesterday at the 2019 European Society for Medical Oncology (ESMO) Congress reported positive results from a Phase 3 clinical trial testing the PARP-inhibitor olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have alterations  in certain DNA damage repair (DDR) genes; a result which will likely lead to a new FDA-approval.  Roughly 20-30% of mCRPC patients harbor these DDR gene mutations in their tumors and thus may benefit from PARP-inhibition.  This trial of olaparib is the first positive Phase 3 “precision medicine” clinical trial testing a targeted therapy in men with advanced prostate cancer with specific mutations.

PARP-inhibitors, including olaparib, are a new class of therapies that are FDA-approved for the treatment of breast and ovarian cancers with mutations in the BRCA1 and BRCA2 genes.  BRCA1 and BRCA2 are critical DNA damage repair (DDR) genes – genes that act to mend any damaged DNA.  Mutations in BRCA genes render cells highly susceptible to acquiring other mutations and developing into cancer.  However, in order to survive, cancer cells that have lost BRCA1, BRCA2 or many other DNA repair genes become dependent on the function of a protein called PARP to maintain sufficient integrity of their DNA.  Thus, cancer cells with mutations in BRCA1/2 are highly sensitive to PARP-inhibiting drugs, with this being an Achilles’ heel and vulnerability for these tumor cells.

The BRCA1/2 genes first became infamous for their association with breast and ovarian cancer, as mutations in these genes are major drivers of these women’s cancers.  Germline (inherited) mutations in BRCA1 or BRCA2 significantly increase a woman’s risk for developing these cancers sometime in their lives. PARP-inhibitors were first FDA-approved as treatments for BRCA1/2-deficient breast and ovarian cancer in 2014.  However, Prostate Cancer Foundation (PCF)-funded studies demonstrated that BRCA1/2 and PARP are also important in prostate cancer.

Early data that PARP may be an important treatment target in prostate cancer came from a PCF-funded team led by Dr. Karen Knudsen, of Thomas Jefferson University.  This team provided preclinical evidence that PARP is a critical driver of prostate cancer and that PARP-inhibitors can suppress prostate tumor growth and progression to CRPC.

In 2015, the PCF International Prostate Cancer Dream Team published a landmark study demonstrating that up to a third of mCRPC cases have mutations in BRCA1, BRCA2, and a number of other DDR genes, such as ATM.  This study was momentous, as it provided rationale for testing PARP-inhibitors as a precision medicine treatment in prostate cancer with DDR gene mutations.  Moreover, the PCF Dream Team found that ~12% of men with metastatic prostate cancer had germline mutations in DDR genes (most frequently in BRCA2) which likely drove the development of their cancer – a finding that rapidly changed NCCN guidelines for prostate cancer germline genetic testing, and has significant implications for cancer screening and risk in both male and female family members of men who carry these genes.

Led by Dr. Johann de Bono, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in the UK, and colleagues, the PCF International Dream Team quickly applied all of these findings in the clinic.  The team initiated a Phase 2 clinical trial, TOPARP, which demonstrated that olaparib had anti-tumor activity in mCRPC patients with DDR gene alterations.  These findings resulted in olaparib receiving a FDA “Breakthrough Therapy Designation” for the treatment of mCRPC with BRCA1/2 or ATM gene mutations.

“Support from the PCF was critically important to making this academic research trial serving this patient population happen, at a time when the pharmaceutical industry was not interested in studying these drugs for men suffering from prostate cancer,” said de Bono.

Dr. Maha Hussain
Dr. Maha Hussain

At the 2019 ESMO Congress Presidential Session, PCF-funded investigator and PCF Dream Team member Dr. Maha Hussain,  Deputy Director, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, presented results from the randomized Phase 3 PROfound trial, which tested olaparib versus physician’s choice of either abiraterone (Zytiga) + prednisone or enzalutamide (Xtandi) in men with mCRPC who failed prior treatment with abiraterone + prednisone or enzalutamide, and who were found to have a mutation in a DDR gene.  Because BRCA1, BRCA2, and ATM mutations were the best characterized genes at the time of the study design , this trial prospectively grouped patients into those with BRCA1, BRCA2, or ATM mutations (cohort A), and those with mutations in any of 12 other predetermined DDR genes (cohort B; BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L).

Overall, 4,425 men were pre-screened internationally for DDR gene alterations in their tumors, and 387 were enrolled onto the trial: 245 in Cohort A and 142 in Cohort B.  In each cohort, patients were randomized 2:1 to receive olaparib vs. physician’s choice of abiraterone or enzalutamide.  The patients on this trial had been heavily pretreated: all had been treated with either abiraterone (40%), enzalutamide (41%) or both (19%), and 66% had previously been treated with taxane chemotherapy (docetaxel, cabazitaxel, or both).

Olaparib significantly delayed the time to radiographic disease progression (tumors growing on scans) or death (whichever came first) compared with abiraterone or enzalutamide, by an average of 3.84 months (7.39 months vs. 3.55 months) in Cohort A (BRCA1, BRCA2, or ATM mutations),  and by an average of 2.3 months (5.82 months vs. 3.52 months) in Cohorts A+B combined (mutations in any qualifying DDR gene).   This represents a reduction in risk of metastatic disease progression or death by 66% in Cohort A, and by 51% in Cohorts A+B.  At 12-months post-enrollment, 40% of men in Cohort A who received olaparib had no radiographic disease progression vs 11% of men who had received abiraterone or enzalutamide.

Response rates, a measure of tumor shrinkage on scans, could be determined for men who had metastatic sites considered measurable at the start of treatment.  Overall, in men with measurable disease in Cohort A, 33.3% who received olaparib responded, while only 2.3% who received abiraterone or enzalutamide responded.  In men with measurable disease in Cohorts A+B, 21.7% who received olaparib responded and 4.5% who received abiraterone or enzalutamide responded.

Olaparib prolonged overall survival by an average of 3.39 months (18.5 vs 15.11 months) in Cohort A (36% reduction in risk of death), and by 3.25 months (17.51 vs 14.26 months) in Cohorts A+B (33%   reduction in risk of death), despite 80% of the men in the control arm crossing over to receive olaparib as soon as they progressed on abiraterone or enzalutamide.  However, the data from the trial is still not mature enough to definitively conclude whether olaparib prolongs overall survival.

Olaparib also significantly delayed the average time to pain progression by 56% in Cohort A, and by 36% in Cohorts A+B.

Across both cohorts A and B, adverse events were more common in patients receiving olaparib vs abiraterone or enzalutamide (95.3% vs. 87.7% for adverse events of any grade; 50.8% vs 37.7% for grade 3 adverse events).  However, patients on olaparib received treatment for a longer time (an average of 7.4 vs. 3.9 months), which may have contributed to higher rates of side effects.  Grade 3 adverse events occurring in patients who received olaparib included anemia (21.5%), fatigue and physical weakness (2.7%), vomiting (2.3%), difficult or labored breathing (2.3%), urinary tract infection (1.6%), nausea (1.2%), and decreased appetite (1.2%).   4.3% of patients who received olaparib experienced a non-fatal pulmonary embolism (vs. 0.8% who received abiraterone or enzalutamide).  Overall, physicians considered olaparib to be well-tolerated.

Dr. Johann de Bono
Dr. Johann de Bono

So how many patients may benefit from this new precision therapy?  In a separate ESMO presentation, de Bono, who co-led the PROfound trial with Hussain, reported on the prevalence of DDR mutations among the patients pre-screened for enrollment onto the PROfound trial.  Of 4,426 mCRPC patients who were initially screened, genomic testing of primary or metastatic tumor samples was performed in 4,047 patients. Testing was successful and could be interpreted in 2,792 patients (69%).   Overall, 17.1% of successfully tested patients had a Cohort A mutation (BRCA2, BRCA1, ATM), and 28% had a mutation in any one of the 15 DDR genes being tested for (Cohort A+B).  The most commonly mutated DDR gene was BRCA2 (8.7%) — and patients with BRCA2 mutations were also the most likely to benefit from treatment with olaparib.  More studies are needed to better define which mutations in which genes are most likely to render prostate cancer sensitive to treatment with olaparib.

In addition to olaparib, three other PARP-inhibitor drugs are currently in Phase 3 clinical trials in prostate cancer: rucaparib (Rubraca), talazoparib (Talzenna), and niraparib (Zejula).   Trials are also testing PARP-inhibitors in all prostate cancer patients (regardless of the presence or absence of DDR gene mutations) and in combination with other treatments, including immunotherapies and radionuclide therapies.

The Prostate Cancer Foundation is proud to have funded the foundational studies that provided the biologic and clinical rationale for this clinical trial.  These practice-changing findings will result in a new precision medicine treatment option for many men with advanced prostate cancer.  A significant proportion of the PCF research portfolio is dedicated to funding research into new precision medicines, such that all men with advanced disease will have additional effective treatment options.

Andrea Miyahira
Dr. Andrea Miyahira has a PhD in cancer immunology, and is Director of Research at the Prostate Cancer Foundation.