Metastatic castration-resistant prostate carcinoma: Positive results from Phase 3 study

Therapy with olaparib prolonged PFS in severely pretreated patients with mCRPC and defective DNA repair mechanisms by approximately 4 months compared to enzalutamide or abiraterone therapy.

First genetic testing and targeted therapy successful

Therapy with the PARP inhibitor olaparib prolonged progression-free survival in severely pretreated patients with metastatic castration-resistant prostate cancer and defective DNA repair mechanisms by approximately 4 months compared to hormone therapy with enzalutamide or abiraterone.

The findings were the result of the phase 3 PROfound study presented by Maha Hussain, from the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (USA) at the ESMO Congress 2019 in Barcelona.

Despite significant advances in systemic therapy,  metastatic castration-resistant prostate cancer (mCRPC) is often lethal. mCRPC is a heterogeneous disease; up to 30% of tumors have mutations in DNA damage repair genes, including genes that play a direct or indirect role in homologous recombination repair (HRR). These genes, such as BRCA1, BRCA2 or ATM, may be sensitive to PARP inhibitors.

Therefore, the randomized open-label phase 3 study PROfound investigated the efficacy and tolerability of the PARP inhibitor olaparib (300 mg twice daily) compared to abiraterone or enzalutamide in men with mCRPC who had progressed after treatment with abiraterone or enzalutamide. Cohort A included 235 men with BRCA1, BRCA2 or ATM mutations (162 received olaparib, 83 an anti-androgen), Cohort B included 142 men with changes in 12 other genes (94 received olaparib, 48 an anti-androgen).

rPFS extended by 4 months

The primary endpoint was radiographic proven progression-free survival (rPFS) in cohort A. This was achieved. rPFS was 7.4 months median for olaparib in patients with BRCA1, BRCA2 or ATM mutations and 3.55 months median for anti-androgen therapy (hazard ratio 0.34, p < 0.0001). The PARP inhibitor thus delayed disease progression by about 4 months. The rPFS rate at 6 months was 59.8% with the PARP inhibitor and 28.1% at 12 months, and 22.6% and 9.4%, respectively, with anti-androgen therapy. Data available to date suggest that overall survival was also prolonged.

The overall response rate (ORR) was significantly higher in the olaparib group (33.3%) than in the anti-androgen group (p < 0.0001) and the time to pain progression was significantly longer with olaparib (2.3%).

Adverse effects of severity 3 or higher were more frequent among olaparib with 50.8% than among antiandrogens with 37.7%. Dose reduction due to side effects was required in 22.3% of patients with olaparib and discontinuation in 16.4% of patients with olaparib. Common side effects of olaparib were anemia, nausea, fatigue, and asthenia.

"Such a significant effect on disease progression and other clinically relevant effects such as pain progression and response are remarkable in such severely pretreated patients with prostate cancer," Hussain said in an ESMO press conference. She continued: "PROfound is the first positive biomarker-controlled Phase 3 study to investigate targeted therapy in men with metastatic castration-resistant prostate cancer.

Careful monitoring is necessary

Elena Efstathiou, from the MD Anderson Cancer Center, Houston, USA, in her role as the presidential symposium study discussant at the ESMO Congress, called PROfound a "landmark" study. Efstathiou observed that the delay in progression by olaparib is significantly greater than the 35-40% improvements achieved to date in this advanced stage of the disease. She also stressed that "significant side effects, such as anemia and nausea, which are more common with olaparib because they can affect the patient when taking the drug, should not be ignored". In any case, patients should be carefully monitored. The data showed that prostate cancer, such as breast cancer and lung cancer, is not a uniform disease. It is necessary to identify the different patient groups and then treat them specifically.

Hussain M, 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. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA12_PR.