Olaparib delays progression in pretreated mCRPC patients with HRR gene alterations
Metastatic castration-resistant prostate cancer (mCRPC) is a molecularly heterogeneous disease, yet current treatments are not based on molecular stratification. Results of the PROfound trial, presented recently at the European Society for Medical Oncology (ESMO) Congress 2019, showed that the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib delays disease progression and improves overall response rate (ORR) in mCRPC patients with alterations in homologous recombination repair (HRR) genes.
“Data suggest that up to 30 percent of mCRPC cases harbour deleterious alterations in DNA damage repair genes, including those with direct or indirect roles in HRR, with BRCA1, BRCA2 and ATM alterations being the most well characterized,” said study author Professor Maha Hussain of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, US. [Cell 2015;161:1215-1228; N Engl J Med 2016;375:443-453; JCO Precis Oncol 2017, doi: 10.1200/PO.17.00029]
“Alterations in HRR genes have been shown to confer sensitivity to PARP inhibition. Antitumour activity with PARP inhibitors, in particular olaparib, has been reported in patients with mCRPC harbouring these alterations,” she noted. [Abida W, et al, ESMO 2018, abstract 793PD]
PROfound is a randomized, open-label, phase III trial evaluating the efficacy and safety of olaparib vs physician’s choice of new hormonal agent (pcNHA) (enzalutamide or abiraterone) in patients with mCRPC with alterations in any of 15 predefined genes with a direct or indirect role in HRR, whose disease has progressed on prior NHA therapy, namely, enzalutamide or abiraterone plus prednisone. [Hussain M, et al, ESMO 2019, abstract LBA12_PR]
Patients were divided into two cohorts based on their genomic alterations. Cohort A (n=245) included patients with alterations in BRCA1, BRCA2 and/or ATM, while cohort B (n=142) comprised patients with alterations in one or more of the remaining 12 predefined HRR genes (BARD1, BRIP1, CDK12, CHEK1, CHECK2, FANCL, PALP2, PPP2R2A, RAD51B, RAD51C, RAD51D and/or RAD54L). The patients were randomized 2:1 to receive olaparib 300 mg twice daily or pcNHA.
The trial’s primary endpoint was radiographic progression-free survival (rPFS) in cohort A, based on the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria by blinded independent central review (BICR).
Key secondary endpoints were rPFS in the overall population, as well as confirmed radiographic objective response rate (ORR), time to pain progression and overall survival (OS) in cohort A.
“Olaparib demonstrated a statistically significant and very clinically meaningful delay in disease progression, with a median rPFS of 7.39 months among patients with BRCA1, BRCA2 or ATM mutations [Cohort A] vs 3.55 months in the pcNHA arm [hazard ratio (HR), 0.34; 95 percent confidence interval (CI), 0.25 to 0.47; p<0.0001], which translates into a 66 percent reduction in the risk of disease progression,” said Hussain. (Figure)
In the overall population of patients with alterations in any of the qualifying HRR genes, the median rPFS was 5.82 months in the olaparib arm vs 3.52 months in the pcNHA arm (HR, 0.49; 95 percent CI, 0.38 to 0.63; p<0.0001).
Confirmed ORR was improved by more than 30 percent with olaparib in cohort A (33.3 percent vs 2.3 percent; odds ratio [OR], 20.86; 95 percent CI, 4.18 to 379.18; p<0.0001). In the overall population of patients with alterations in any of the qualifying HRR genes, the ORR was 21.7 percent with olaparib vs 4.5 percent with pcNHA (OR, 5.93; 95 percent CI, 2.01 to 25.40; p<0.0001).
“Preliminary data also showed that olaparib treatment prolonged OS by more than 3 months vs enzalutamide or abiraterone in the overall population of patients with alterations in any of the qualifying 15 HRR genes,” said Hussain.
Interim analysis at 38 percent data maturity showed a trend towards improved OS in cohort A with olaparib vs pcNHA (median, 18.50 months vs 15.11 months; HR, 0.64; 95 percent CI, 0.43 to 0.97; p=0.0173).
Time to pain progression was also improved in cohort A with olaparib vs pcNHA (median, not reached vs 9.92 months; HR, 0.44; 95 percent CI, 0.22 to 0.91; p=0.0192).
Two-thirds of the study participants had received prior taxane treatment, with approximately one-fifth having been exposed to both docetaxel and cabazitaxel. One-fifth of the patients (19.9 percent in the olaparib arm and 17.6 percent in the comparator arm) had received both enzalutamide and abiraterone previously.
“To see such a significant effect on disease progression and other clinically relevant effects, such as pain progression and ORR, is a remarkable achievement in such heavily pretreated patients with prostate cancer,” commented Hussain.
“Olaparib was generally well tolerated and its safety profile was consistent with what was previously established,” stated Hussain.
Olaparib-treated patients had a higher incidence of adverse events (AEs) (grade ≥3, 50.8 percent vs 37.7 percent) as well as dose reductions due to AEs (22.3 percent vs 3.8 percent) and treatment discontinuations due to AEs (16.4 percent vs 8.5 percent) vs pcNHA-treated patients.
“The duration of treatment with olaparib was longer than with enzalutamide or abiraterone [7.4 months vs 3.9 months],” noted Hussain.
In the trial, olaparib’s most common AEs were anaemia (46.5 percent vs 15.4 percent), nausea (41.4 percent vs 19.2 percent), decreased appetite (30.1 percent vs 17.7 percent), and fatigue and asthenia (41.0 percent vs 32.3 percent). “Apart from anaemia, for which 21.5 percent of patients reported grade ≥3 events, the vast proportion of other AEs were of low grade,” noted Hussain.
“Of note, while the median age of 69 years is quite usual for mCRPC trials, PROfound also included patients in their late 80s and even early 90s, pointing to the feasibility of olaparib treatment in a broader population,” commented Hussain.
“Prostate cancer has lagged behind all other common solid tumours in the use of molecularly targeted treatment. It is therefore very exciting that we can now personalize treatment based on specific genomic alterations in patients’ cancer cells,” said Hussain.
“In patients with mCRPC with disease progression on prior new hormonal agents, olaparib provided a statistically significant and clinically meaningful improvement in rPFS, ORR and time to pain progression compared with physician’s choice of enzalutamide or abiraterone,” said Hussain. “Despite an over 80 percent crossover rate, at interim analysis, olaparib maintained a favourable trend in OS for patients with alterations in BRCA1, BRCA2 or ATM, as well as in the overall study population.’”
“PROfound is the first positive biomarker-selected phase III trial evaluating a molecularly targeted therapy in men with mCRPC, demonstrating that precision medicine trials are feasible in prostate cancer and highlighting the importance of genomic testing for these patients,” concluded Hussain.