Targeting DNA Repair Defects With Olaparib Improves rPFS in mCRPC

In an interview with Targeted Oncology, Maha Hussain, MD, discussed targeting DNA repair defects in metastatic castration-resistant prostate cancer with the PARP inhibitor olaparib in the phase III PROfound trial.

Maha Hussain, MD

The investigators of the phase III PROfound trial found that targeting specific gene alterations with olaparib (Lynparza) improved radiographic progression-free survival (rPFS) compared with the physician’s choice of enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in patients with metastatic castration-resistant prostate cancer (mCRPC). This demonstrated a positive step toward precision medicine in prostate cancer, according to Maha Hussain, MD.

The initial screening included 4425 men with mCRPC. Once screened, these patients were divided into 2 cohorts. Cohort A (n = 245) included patients with alterations inBRCA1,BRCA2,orATM. Patients in cohort B (n = 142) had any of 12 other alterations including:BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L. These patients were randomized 2:1 to receive olaparib versus enzalutamide or abiraterone, according to the physician’s choice. The primary endpoint was rPFS in cohort A, which was the main focus of the trial.

The cohorts were also evaluated for secondary endpoints, such as confirmed objective response rate (ORR), time to pain progression (TTP), and overall survival (OS).

The median rPFS was longer in cohort A at 7.39 months (HR, 0.34; 95% CI, 0.25-0.47;P<.0001), compared with 5.82 months in cohort B (HR, 0.49; 95% CI, 0.38-0.63; P<.0001). ORR was also improved in patients who received olaparib. Cohort A showed a 33.3% ORR and cohort B had a 21.7% ORR.

Once the trial data matured, patients in cohort B (84.6%) who progressed on either enzalutamide or abiraterone were allowed to crossover to olaparib.

Having shown improvement in rPFS, ORR, and good OS trends, the PROfound trial is the first phase II study to select biomarkers to target subsets of mCRPC, according to the investigators.

In an interview withTargeted Oncology,Hussain, the Genevieve Teuton Professor of Medicine, Division of Hematology/Oncology, Department of Medicine, and deputy director, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, discussed targeting DNA repair defects in mCRPC with the PARP inhibitor olaparib in the phase III PROfound trial.

TARGETED ONCOLOGY: What was the rationale for the PROfound trial?

Hussain: The rationale for the PROfound trial was to evaluate the role of targeting DNA repair defective tumors with a PARP inhibitor. This started years ago when there were emerging data regarding the subpopulation of castration-resistant disease. Data from Stand Up to Cancer suggested that about 25% of patients have DNA repair defects in their tumors, which makes them particularly susceptible to PARP inhibition.

Then, there were emerging data from clinical trials, specifically with olaparib with TOPARP, looking at olaparib for mCRPC in the second line. It demonstrated efficacy, and interestingly, the efficacy—as measured by prostate-specific antigen (PSA) declines, response rates, and PFS—was specifically in the cohort of patients who had DNA repair defects, which the drug is targeting. There were other emerging data from other settings, and it seemed like the perfect time to ask the question prospectively.

TARGETED ONCOLOGY: What was the design of the trial?

Hussain: The trial was designed to look at 2 cohorts and this was driven by the fact that the bulk of the data that we have, with regard to PARP inhibitors’ efficacy in other cancers, is primarily in theBRCA1/BRCA2orATMgenes, and looking at rPFS. From a clinical benefit perspective, this has been an established endpoint with regard to defining clinical benefit, and even for the purpose of potential FDA approvals. Radiographic PFS was the primary endpoint. The secondary endpoints included the overall radiographic PFS in the overall population, in cohorts A and B; then, we also looked at measurable disease response rate, PSA declines, TTP, and a variety of other secondary endpoints. The driver, however, is cohort one, in regard to the primary endpoint and the statistical design. The rPFS across the board was validated by a central blinded radiographic evaluation.

TARGETED ONCOLOGY: What was the prevalence of these mutations?

Hussain: Overall, the prevalence at this moment looks like it is in the high 20s when you're looking at patients from the primary biopsy and goes up to 31% for metastatic disease. This is a very important observation because, for a long time, we used to feel that metastatic disease has to be the sight of tissue evaluation. Even in my practice, I always went for metastatic disease. Now, seeing these data, I would say look at the primary tissue if it's available, and if the tissue is negative, that's where I would air on the side of performing a biopsy on metastatic disease.

TARGETED ONCOLOGY: Was olaparib effective in this patient population?

Hussain: Yes. The benefit was pretty remarkable in that rPFS was significantly delayed. In the primary cohort (cohort A), it's almost double the control. The control was active treatment with either abiraterone or enzalutamide per physician's choice.

It also showed similar trends and benefit in the overall population. From my end, what was also impressive is the fact that the measurable disease responses were much higher at about 30% by comparison to much lower numbers in the control group.

The other part that's very important from a clinical perspective is that pain progression was significantly delayed. In fact, the medians have not yet been reached in the olaparib arm. Then, the early trends on OS are also very encouraging. We have not had an adequate number of deaths to declare a final result. But the curves began separating early, and it looks very promising.

TARGETED ONCOLOGY: What are the implications of these findings?

Hussain: The implications come at multiple fronts. From a patient perspective, I am delighted to say that we have one more agent in the portfolio of treatments for patients. This portfolio has expanded rapidly over the years. The beauty of this is that it is achieving a metric that we have not reached in prostate cancer, which is precision medicine, of tailoring treatment to the patient's tumor.

From the big-picture perspective, I would say that historically, there have not been enough targeted therapy trials in prostate cancer with pre-selected populations. This shows that it's feasible, doable, and it can be achieved in a short period of time, this was actually accomplished in a relatively short period of time. It's fantastic news for patients and physicians, and I think it opens up the door to much more accelerated research that is more personalized. My hope is that we will begin to develop combination treatments and look at other targets.

TARGETED ONCOLOGY: In your opinion, what are the next important targets?

Hussain: There are several emerging targets but it's not clear whether we have the right drugs for them. That's where the complexity comes in.

There are pathways like PTEN, AKT, and so on, where there are drugs that work indirectly. The androgen receptor continues to be a dominant player in the picture. Also, using immune therapy and figuring out ways of pre-selecting patients for appropriate immune treatment is some of the work that's needed.

I think that the sky is the limit and we have come a long way in a short time. The first drug to prolong life in prostate cancer was docetaxel in 2004. Now, 15 years later we have a big portfolio. We have not yet achieved the benchmark, which is trying to cure this cancer. But the acceleration has been fantastic in terms of better drugs.


Hussain M, Mateo J, Saad F, et al. PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Presented at: 2019 ESMO Congress; September 27-October 2, 2019; Barcelona, Spain. Abstract LBA12_PR.