PROfound: What the Prostate Cancer Trial Found

The idea behind the trial

Cells repair broken DNA constantly. One repair system is called homologous recombination repair, or HRR. BRCA1, BRCA2, and ATM are among the genes that run it.

When an HRR gene is faulty, the cell leans harder on a backup repair route that depends on an enzyme called PARP. Block PARP in a cell that has already lost HRR, and damage accumulates until the cell dies. Cells with working HRR survive, because they still have the main system.

Olaparib is a PARP inhibitor. That logic had already changed treatment in ovarian and breast cancer. PROfound asked whether it held in prostate cancer.

How PROfound was built

PROfound was a randomized, open-label phase 3 trial. Its ClinicalTrials.gov record, NCT02987543, lists 387 participants.

All were men with metastatic castration-resistant prostate cancer. Castration-resistant means the cancer kept growing despite treatment that lowers testosterone. All had already progressed on a newer hormonal agent — enzalutamide or abiraterone.

Every man had a qualifying gene alteration, determined centrally from tumor tissue rather than assumed.

They were split into two cohorts before randomization.

Cohort A, 245 men, had at least one alteration in BRCA1, BRCA2, or ATM. Cohort B, 142 men, had alterations in any of 12 other prespecified HRR genes.

Within each cohort, men were randomized 2 to 1 to olaparib or to the physician's choice of the other hormonal agent they had not already failed.

The primary endpoint was imaging-based progression-free survival in cohort A, judged by blinded independent central review.

What it found

In cohort A, median imaging-based progression-free survival was 7.4 months with olaparib and 3.6 months with the control.

The hazard ratio for progression or death was 0.34, with a 95% confidence interval of 0.25 to 0.47 and a p-value below 0.001.

Olaparib also improved the confirmed response rate and delayed the point at which pain worsened. That second measure is easy to skip past and hard to overvalue: in advanced prostate cancer, pain is often what limits a day.

Progression-free survival also favored olaparib across cohorts A and B combined.

The survival question

Overall survival was reported separately, in a 2020 paper by Hussain and colleagues.

In cohort A, median overall survival was 19.1 months with olaparib and 14.7 months with the control. The hazard ratio for death was 0.69, with a 95% confidence interval of 0.50 to 0.97 and a p-value of 0.02.

In cohort B it was 14.1 months versus 11.5 months. Across both cohorts, 17.3 months versus 14.0 months.

Crossover complicates all of this. Sixty-six percent of the control group — 86 of 131 men — crossed over to olaparib after their disease progressed. In cohort A it was 67%.

The authors ran a sensitivity analysis adjusting for that. It produced a hazard ratio for death of 0.42 in cohort A. Their conclusion was that the survival benefit held despite substantial crossover.

What it costs

The main toxic effects with olaparib were anemia and nausea.

Anemia is the one that shapes daily life. It arrives as fatigue and breathlessness rather than as anything dramatic, and it is why blood counts are checked regularly on this drug.

What happened next

On 19 May 2020 the FDA approved a supplement to olaparib's application, NDA 208558 supplement 14.

The indication is precise: adults with deleterious or suspected deleterious germline or somatic HRR gene-mutated metastatic castration-resistant prostate cancer who have progressed after prior treatment with enzalutamide or abiraterone.

Germline means inherited and present in every cell. Somatic means acquired and present only in the tumor. The approval covers both, which is why testing tumor tissue matters and not only family history. Our page on genetic testing for cancer risk covers the difference.

When to get checked

For anyone taking a PARP inhibitor, worsening fatigue, breathlessness on stairs, or unusual paleness should prompt a blood count rather than a wait-and-see.

For prostate cancer, NCI lists early urinary symptoms — trouble starting the flow, frequent urination especially at night, trouble emptying the bladder, and a weak or stop-and-go stream. Those are far more often caused by a benign enlarged prostate.

The advanced list is different: back, hip, or pelvic pain that does not go away, and breathlessness, deep fatigue, fast heartbeat, dizziness, or pale skin from anemia.

One request is worth making explicitly. Any man diagnosed with metastatic prostate cancer should ask whether his tumor has been tested for BRCA and other HRR gene alterations, and whether germline testing is appropriate. A positive result changes his own options and may matter for his relatives. Our overview of prostate cancer covers the wider picture.

The population this describes

About 333,830 new prostate cancer diagnoses and 36,320 deaths are estimated for the United States in 2026 — an American Cancer Society projection, shown on the SEER prostate page. The median age at diagnosis is 68.

Sixty-nine percent is localized at diagnosis and 14% regional, with five-year relative survival at essentially 100% for both. Nine percent is distant, with five-year relative survival of 40.1%.

Across all stages, five-year relative survival is 98.2% for men diagnosed from 2016 through 2022. That figure is driven by the large early-stage group. It does not describe the men in PROfound, all of whom had metastatic disease that had already stopped responding to hormonal treatment.

What this trial cannot tell you

The control arm is the trial's weak point. Men were given a second hormonal agent after the first had already failed — a treatment known to work poorly in that situation. Beating it is a lower bar than beating an active alternative such as chemotherapy.

The trial was open-label. Central blinded review of scans limits the damage on the primary endpoint but does not remove it from everything else.

Crossover makes the survival comparison harder to read, even with the adjusted analysis.

And the benefit was concentrated. It was driven mainly by men with BRCA alterations rather than spread evenly across every gene on the panel. The cohort B numbers are noticeably weaker than cohort A's.

Sources

• de Bono J et al., N Engl J Med 2020, PROfound (NCBI E-utilities)
• Hussain M et al., N Engl J Med 2020, PROfound survival (NCBI E-utilities)
• FDA supplement approval letter, NDA 208558/S-014 (Lynparza), 2020
• ClinicalTrials.gov record for NCT02987543 (PROfound)
• NCI PDQ: Prostate Cancer Treatment (Patient Version)
• NCI SEER Stat Facts: Prostate Cancer

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

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