Not All Prostate Cancer Mutations Created Equal for Olaparib

Liam Davenport

September 22, 2020

The poly-ADP ribose polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca) significantly improves survival in pretreated metastatic castration resistant prostate cancer (mCRPC) patients carrying BRAC1/2 mutations, suggests final overall survival data from PROfound.

However, a lack of survival benefit with the drug in men carrying other homologous recombination repair (HRR) gene mutations may impact its clinical application and limit its availability.

The research was presented at the ESMO Virtual Congress 2020 on September 20, held digitally this year due to the COVID-19 pandemic, and simultaneously published in The New England Journal of Medicine.

Royal Marsden Research

Prof Johann de Bono

For PROfound, Professor Johann de Bono, of the Royal Marsden Hospital, London, and colleagues, randomised 387 patients with mCRPC that had progressed on hormonal therapy to either olaparib or physician's choice from enzalutamide or abiraterone.

Interim results in a cohort of patients with BRCA1, BRCA2, or ATM mutations presented at the ESMO Congress in 2019 indicated that olaparib was associated with significant improvements in progression-free survival.

As reported by Medscape Medical News, preliminary overall survival data also suggested that the PARP inhibitor extended survival by more than 3 months.

Olaparib was subsequently approved by the US Food and Drug Administration for use in men with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone.

Latest Data

Now, final overall survival data from the cohort of patients with BRCA1, BRCA2, or ATM mutations showed that olaparib improved survival by 30%, or more than 4 months, over enzalutamide or abiraterone therapy.

This was despite a crossover rate from the control to active treatment arm of 67%.

In patients with mutations in twelve other HRR genes of interest, the improvement in overall survival was not significant, meaning that across the whole study population, the benefit with olaparib was of marginal significance.

Study co-author Dr Joaquin Mateo, Vall d'Hebron Institute of Oncology and Vall d'Hebron University, Barcelona, Spain, said that "additional studies may be required to further delineate genomic indicators of PARP response, particularly for those with less common gene alterations".

Nevertheless, with no new safety signals detected, he said that "PROfound is the first randomised trial to prospectively demonstrate overall survival improvement in a molecularly defined subset of prostate cancer".

The results therefore support "the implementation of genomic testing in daily clinical practice".

'Hugely Exciting'

Dr Matthew Hobbs, director of research at Prostate Cancer UK, commented that the results are "hugely exciting" and "represent a revolution in the treatment of prostate cancer".

"Until now, treatment for advanced disease has been essentially one-size-fits- all," he said. "But for the first time ever, olaparib gives us the opportunity to treat men based on the genetic make-up of their cancer.

"These results offer the final proof needed that this treatment not only slows down the cancer's progression, but also improves overall survival, giving men more valuable time with their families."

While underlining the further research the charity is funding to expand precision treatment, Matthew Hobbs said that "our immediate priority is to make sure olaparib, and the tests needed to find the men who stand to benefit from this drug, are made available as quickly and widely as possible across the UK".

'Not Every Mutation Is Equal'

The limited activity seen in mutations other than BRCA1 and BRCA2, including ATM, which was one of the main genes of interest in the study, did not go unnoticed, however.

Dr Álvaro Pinto, a medical oncologist at Hospital Universitario La Paz in Madrid, Spain, said that the trial "confirms the role of PARP inhibitors" in mCRPC.

But he underlined that it also shows that "not every mutation is equal" with activity seemingly "restricted to BRCA1/2 alterations".

Indeed, on the strength of the current analysis, the European Medicines Agency (EMA) issued a recommendation last week that the indication for olaparib in mCRPC be for patients carrying BRCA1/2 mutations.

Dr Mateo stressed in the post-presentation debate, however, that despite the equivocal overall results, some patients with ATM mutations "are benefitting," and "it may be that many are benefiting but in a smaller amount, that is what we still have to understand better".

As for the more exploratory cohort B, he said that many of the mutations were found in previous studies to "associate very well with sensitivity to these agents" but their rarity means that only small numbers of patients could be recruited into PROfound.

Consequently, "it's very difficult to interpret cohort B as a whole and actually it's a sum of different individual situations".

Other Patient Groups

Dr Mateo added that the EMA focusing solely on men with BRCA1/2 mutations means that "you are also leaving other men behind who actually could be benefiting but are not represented well enough".

"As the patient advocate I remain very concerned that men with non-BRCA alterations that are sensitive to these drugs…may not receive them when the more conservative physician focuses only on BRCA," said Prof de Bono, who also took part in the debate.

"There are undoubtedly other patients with other alterations…that respond to these agents. Perhaps combinations will be needed for certain but we must not fail these men who have very little other options."

Presenting the findings, Dr Mateo noted that more than "20% of all metastatic prostate cancers harbour somatic or germline deleterious mutations in DNA repair genes".

For PROfound, they "prospectively selected patients with mutations in one of fifteen prespecified genes using a tissue based targeted next generation sequencing assay".

The patients, all of whom had mCRPC that had progressed on previous hormonal therapy, were stratified into those with BRCA1/2 or ATM mutations (cohort A) and those with any of the other twelve preselected mutations (cohort B).

They were then randomised in a 2:1 fashion to olaparib 300 mg twice daily or a control arm comprising physician's choice from enzalutamide or abiraterone plus prednisone.

If patients in the control arm experienced radiographic disease progression on blinded independent central review and had received no subsequent anticancer therapy and no toxicities from previous therapy, they were allowed to cross over to the olaparib arm.

The results showed that, in cohort A, overall survival was significantly improved with olaparib, at a median of 19.1 months versus 14.7 months for patients in the control arm or a hazard ratio of 0.69 (p=0.0175).

When adjusting for crossover, the team found that the hazard ratio decreased further to 0.42.

In contrast, there was no significant difference in overall survival between olaparib and control arms in cohort B, at a median of 14.1 months and 11.5 months, respectively, or a hazard ratio of 0.96.

Adjusting for crossover had only a marginal effect on the hazard ratio, reducing it to a non-significant 0.83.

Across the whole study population, there was a trend for significance in favour of olaparib, at a median overall survival of 17.3 months compared with 14.0 months in the control arm or a hazard ratio of 0.79.

Again, adjusting for crossover reduced the hazard ratio but did not increase the significance of the results.

Exploratory Gene-Level Analysis

Dr Mateo also presented the results of an exploratory gene-level analysis of final overall survival, which showed that the results in patients with BRCA2 mutations were the strongest, and while those for BRCA1 crossed the line of unity the number of patients was small.

However, for patients with ATM, CD12, and CHEK2 mutations, olaparib appeared to have no clinical benefit in terms of overall survival, while the control therapy appeared to have been more effective in those with PPP2R2A mutations.

The numbers of patients in each of those mutational groups were, again, small.

In terms of safety, grade ≥3 adverse events were experienced by 52% of patients in the olaparib arm and 40% in the control arm, with events leading to discontinuation seen in 20% and 8%, respectively.

The most common adverse events in patients treated with olaparib were anaemia (50%), nausea (43%), fatigue (42%), and decreased appetite (31%), while those in the control arm were fatigue (33%), nausea (21%), decreased appetite (18%), and anaemia and constipation (15% each).

Questions were raised over the design of the study.

Dr Paolo Tarantino, from the European Institute of Oncology and University of Milan, Italy, said on Twitter that while olaparib was "surely active" in the patients, there are "some trial flaws" that "deserve discussion".

Henrik Grönberg, professor in cancer epidemiology, Karolinska Institutet, Stockholm, Sweden, who was the invited discussant for the trial, highlighted the control group, for example, as being problematic.

He questioned the decision to put men who had already progressed on hormonal therapy on another hormonal therapy.

"Looking at the response rates and [prostate-specific antigen] response, they were very low in the control group and I think you can conclude that the treatments…were ineffective," he said.

"And I think this has a bearing on how to interpret the overall survival analysis later."

Professor Grönberg also highlighted the high rate of crossover from the control to active treatment group, saying that it also makes it "difficult to evaluate overall survival".

"The authors have done a good job of trying to do that but we need to understand more in detail how this effects the results."

But the final question is inevitably: "Would I treat my patients, based on these data, with olaparib?

"Yes, most likely I would treat my patients with BRAC1 or BRCA2 mutations who have already received standard treatments," Professor Grönberg said. "I think the combined analysis from many studies show this."

As for men carrying mutations in the other genes, the answer is "mostly likely no".

The study was funded AstraZeneca and Merck.

Prof de Bono declares Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy, Licensing/Royalties, Patent WO 20 0 5 0 53662 on DNA damage repair inhibitors for treatments of cancer: AstraZeneca; Advisory/Consultancy: Bayer Healthcare; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Daiichi Sankyo Company; Advisory/Consultancy: Genentech; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy, Licensing/Royalties, Patent US560 4213 on 17 substituted steroids useful in cancer treatment: Janssen Global Services; Advisory/Consultancy: Menarini Silion Biosystems; Advisory/Consultancy: Merck; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Orion Corporation; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Qiagen Sciences; Advisory/Consultancy: Sanofi Aventis US; Advisory/Consultancy: Sierra Oncology; Advisory/Consultancy: Taiho Pharmaceuticals; Advisory/Consultancy: Vertex Pharmaceuticals.

Dr Mateo declares Advisory/Consultancy: Amgen; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Janssen Pharmaceuticals; Speaker Bureau/Expert testimony: Astellas Pharma; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca.

Prof Grönberg declares advisory boards and/or lectures: Astellas Pharma, Janssen Oncology, Bayer Healthcare.

ESMO Virtual Congress 2020: Abstract 610O. Presented September 20.

N Engl J Med 2020. doi: 10.1056/NEJMoa2022485. Paper


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