'Landmark' Trial in Prostate Cancer With Mutations

Liam Davenport

October 04, 2019

BARCELONA, Spain — Using genetic testing to target treatment for patients with advanced prostate cancer has given some "remarkable" results from a phase 3 trial described as a "landmark."

Patients with prostate cancer should now undergo genetic testing of tumor tissue to identify the 30% or so of patients who can benefit — as is already routinely being done for breast, ovarian and lung cancer, say researchers. 

The results come from the phase 3 PROfound study of the PARP inhibitor olaparib (Lynparza, AstraZeneca) in patients who tested positive for DNA repair gene alterations including BRCA1, BRCA2, or ATM mutations.  

These were patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease had progressed after treatment with the newer hormonal agents such as abiraterone (Zytiga, Janssen) or enzalutamide (Xtandi, Medivation and Astellas Pharma), and/or with taxane chemotherapy.

In this study, BRCA1 or BRCA2 alterations were seen in 35% to 40% of patients, while 18% to 24% had ATM alterations and 34% had other alterations. Between 6.6% and 8.4% of patients had more than one alteration.

The new results, presented here at the European Society for Medical Oncology, show olaparib has significant benefit for patients with these gene alterations.

The drug delayed cancer progression by about 4 months compared with new hormonal therapy [NHA], and preliminary data suggest that overall survival was also prolonged, by more than 3 months.

In addition, the response rate was much higher and there was a longer time to pain progression with olaparib.

Dr Maha Hussain

"To see such a significant effect on disease progression and other clinically relevant effects such as pain progression and objective response rate is a remarkable achievement in such heavily pretreated patients with prostate cancer," said principal investigator Maha Hussain, MD, from the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.

"Despite the fact that there was 80% crossover to the olaparib to the control arm, I am delighted to say that PROfound is the first positive-biomarker, selected phase 3 clinical study evaluating a molecular targeted therapy in men with metastatic castration-resistant disease," she commented at a press briefing where the results were highlighted.

Discussant Eleni Efstathiou, MD, PhD, a medical oncologist at MD Anderson Cancer Center, Houston, Texas, described PROfound as a "landmark trial."

She said that the delay in progression seen with olaparib is "impressive because it is considerably higher than the 35% to 40% improvements with which we've been very satisfied in previous prostate cancer studies in this more advanced disease setting."

Although Efstathiou noted the trend toward improved survival, she emphasized that "we need to wait for the final analysis," and underlined that "we should not ignore that significant adverse events, such as anemia and nausea, were more common with olaparib, as these can have an important effect on a patient's ability to take the drug."

"In practice, patients will need to be carefully monitored," she added.

Nevertheless, she said that "these data show that, like breast and lung cancers, prostate cancer is not one but many different diseases and we need to start identifying different groups of patients and treating them with targeted therapy."

Ignacio Duran, MD, PhD, Hospital Universitario Marques de Valdecilla, Santander, Spain, was equally positive in his praise of the trial.

He told the press conference that it offers a "double hit," as a result of not only the "dramatically superior" efficacy with olaparib but also the proof a "new concept" that prostate cancer can be treated with targeted therapy.

"This is the first time we've been able to identify that we can more precisely characterize the molecular biology, the genetic background, of these tumors and that is going to determine how we treat them," he added.

Targeting Genes to Stop Cancer

Hussain explained that the rationale for the PROfound study was based on the realization, over the past 10 years, that some patients with prostate cancer have have deleterious alterations in a variety of genes.

She noted that mCRPC is molecularly heterogeneous, with up to 30% of tumors having deletions in DNA damage repair genes, including those that play a role in homologous recombination repair (HRR).

Some of these alterations can confer sensitivity to PARP inhibition, such as BRCA1, BRCA2, and ATM, and "so the intent here is to target those types of genes to prevent the cancer cell from repairing itself."

To find patients with these genes, the team tested prostate tumor tissue with an investigational clinical trial assay developed in conjunction with Foundation Medicine and based on next-generation sequencing.

The patients were divided into two groups:

  • cohort A, consisting of 245 patients with BRCA1, BRCA2, or ATM gene alterations

  • cohort B, comprising 142 individuals with any of the remaining 12 alterations (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L).

Both cohorts were randomly assigned in a 2:1 fashion to olaparib 300 mg twice daily or physicians' choice of either enzalutamide or abiraterone. Patients in the hormone therapy group who progressed were allowed to crossover to olaparib.

All patients had received previous treatment: both abiraterone and enzalutamide had been given to 17.6% to 19.9% of patients, and 64.1% to 66.4% had previously received taxanes.

The primary endpoint of this study was radiographic progression-free survival (rPFS) in cohort A, and this showed a significant improvement: median rPFS was 7.4 months with olaparib vs 3.6 months with hormonal therapy (hazard ratio for progression, 0.34; P < .0001).

At 6 months, 60% of olaparib patients were progression-free vs 23% of those on hormonal therapy, and this fell to 28% and 9.4%, respectively, at 12 months.

This significant benefit was seen across all subgroups, whether the patients were stratified by previous taxane use, measurable disease at baseline, site of metastases, baseline performance status, age at randomization, geographic location, and baseline prostate-specific antigen levels.

The performance of olaparib was underlined by a confirmed objective response rate of 33.3% in cohort A vs just 2.3% with NHA therapy, at an odds ratio of 20.86 (P <.0001).

Crucially, the time to pain progression, as measured using the Brief Pain Inventory–Short Form, was significantly longer in cohort A with olaparib vs NHA therapy, at a median that was not reached vs 9.9 months, or a hazard ratio [HR] of 0.44 (P = .0192).

When the researchers considered both patient cohorts together, the rPFS was still significantly better for olaparib, which had a median rPFS of 5.8 months vs 3.5 months for hormonal therapy (HR, 0.49; P < .0001).

The survival analysis, which was only 41% mature across the two cohorts at data cutoff, suggested that overall survival was significant longer with olaparib over NHA therapy.

In cohort A, the median overall survival was 18.5 months and 15.1 months, respectively (HR, 0.64, P = .0173).

In both cohorts combined, the median overall survival was 17.5 months and 14.3 months, respectively (HR, 0.67, nominal P = .0063).

These findings, Hussain noted, suggest that there is evidence that olaparib has clinical activity in mCRPC in patients who have alterations in genes other than BRCA1 and BRCA2.

In terms of safety, there were more adverse events with olaparib than hormonal therapy, with 50.8% and 37.7%, respectively, experiencing grade 3 or higher adverse events.

Dose reductions due to an adverse event were also more common with olaparib, at 22.3% vs 3.8% of patients receiving hormonal therapy. Drug discontinuations due to adverse events were similarly greater with olaparib and were seen in 16.4% vs 8.5% of patients.

The most common adverse event with olaparib was anemia, in 21.5%, with fatigue and asthenia seen in just 2.7%. Those two adverse events were also the most commonly seen in hormonal therapy patients, but occurred in just 5.4% of cases for both.

Genetic Testing in Prostate Cancer

Hussain said that the results should encourage the greater use of genetic testing in patients with mCRPC.

She noted that oncologists treating breast, ovarian, or lung cancer are already routinely carrying out genetic testing on tumor tissue, because the results determined which standard of care treatment is most suitable.

For such testing to be taken up more widely in prostate cancer, she said, "We need to begin to educate the community and share information with them regarding the merits of testing…"

The results from the current study are "opening up the door for us right now," she added.

However, there is another issue here, Hussain noted: the gene alterations in this prostate cancer study are germline mutations and this has implications for family members, similar to the issue of BRCA genes in breast cancer.

This is just one of many issues that needs to be addressed in the community, alongside, for example, the use of PARP inhibitors in preselected patients in the frontline setting, as well as in potential combinations of PARP inhibitors with hormonal therapy to see if they may have synergistic effects.

The study was funded by AstraZeneca and Merck Sharp & Dohme. Hussain reports relationships with Sanofi/Genzyme, Genentech, Aptitude Health, Epics, AstraZeneca, Bayer, Pfizer, PER, and Astellas. Other authors have also declared numerous potential conflicts of interest. Duran reports relationships with Roche-Genentech, Bristol-Myers Squibb, MSD, Janssen, AstraZeneca, Seattle Genetics, Pharmacyclics, Bayer, Novartis, Debio Pharma, Astellas, IPSEN, Eisai, Janssen, Roche, and Clovis.

European Society for Medical Oncology (ESMO) 2019 Annual Meeting: Abstract LBA12_PR. Presented September 30, 2019.

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