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Gene-Specific Exploratory Analysis Sheds Light on Lynparza Benefit in HRR-Mutated Prostate Cancer

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NEW YORK – A final overall survival analysis of the Phase III PROfound study presented during the European Society for Medical Oncology's Virtual Congress demonstrates that the PARP inhibitor olaparib (AstraZeneca/ Merck's Lynparza) significantly improves survival outcomes for men with metastatic castration-resistant prostate cancer (CRPC) whose tumors harbor BRCA 1/2 or ATM mutations and who have received previous treatment with a new hormonal agent.

Researchers also presented a post-hoc, exploratory analysis of the PARP inhibitor's effect on patients who harbor alterations in homologous recombination repair genes beyond BRCA1/2.

The PROfound trial randomized 387 patients with metastatic CRPC and HRR gene alterations to receive treatment with either olaparib or physician's choice of either enzalutamide (Pfizer/Astellas Xtandi) or abiraterone (Janssen's Zytiga). The patients were eligible for enrollment if their cancer progressed after treatment with enzalutamide or abiraterone, which meant that patients in the control arm were treated with a drug that has the same mechanism of action that they previously received and progressed on.

The study was designed to evaluate the drug in two cohorts of patients — cohort A included those harboring at least one alteration in BRCA1, BRCA2, or ATM, and cohort B, which included patients harboring alterations in at least one of 12 other pre-specified HRR genes, including BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAF51D, and RAD53L.

Joaquin Mateo of the Vall d'Hebron Institute for Oncology in Barcelona presented the PROfound overall survival results. Among all randomized patients in both cohorts, the median overall survival for patients treated with olaparib was 17.3 months versus 14 months for patients treated with the hormonal agent in the control arm. Broken down by HRR gene mutation status, patients in cohort A treated with olaparib achieved a median overall survival of 19.1 months versus 14.7 months in the control arm, and these figures were 14.1 months and 11.5 months, respectively, in cohort B.  

Gene-level analysis raises questions

In May, based on a previously reported progression-free survival benefit with olaparib, the US Food and Drug Administration approved the agent for patients with metastatic CRPC harboring any of the HRR gene alterations assessed, with the exception of PP2R2A, due to unfavorable risk-benefit. The FDA specified two companion diagnostics — Myriad Genetics's BRCAnalysis CDx and Foundation Medicine's FoundationOne CDx — to identify patients eligible for the drug.

Notably, while the PROfound trial's primary endpoint was radiographic progression-free survival specifically in cohort A, the FDA approved olaparib for patients with HRR gene-mutated metastatic more broadly, based on a statistically significant progression-free survival benefit seen in both cohort A and cohort A and B collectively. Interim overall survival data were only available for cohort A at the time of the approval.

Now, the more recent results reported from PROfound indicate that although olaparib's benefit was significant in the overall patient population, the same was not true of cohort B, which included patients with non-BRCA1/2 HRR gene mutations. "A clinical benefit was not observed for olaparib in the population of patients who had other homologous recombination repair gene alterations [other than BRCA1/2 and ATM]," wrote the authors of the New England Journal of Medicine paper detailing the PROfound final overall survival results, published in tandem with the ESMO presentation. As such, the authors ultimately highlighted the need for "additional studies to further delineate genomic indicators of response to PARP inhibition."

In a discussion following the ESMO presentation of PROfound's overall survival results, Henrik Grönberg of the Karolinska Institutet in Sweden, said definitively that he would not treat patients with HRR mutations outside of BRCA1/2 with olaparib on the basis of PROfound's results.

On the other hand, in an interview discussing her take on the trial, Eleni Efstathiou, a genitourinary cancer expert at the MD Anderson Cancer Center, said she agreed with the FDA's choice to approve olaparib for patients who harbor a broader range of HRR gene alterations as opposed to restricting the drug for those with BRCA1/2 or ATM mutations.

"It's fair that the FDA went for that" broader indication, she said, recognizing that the trial was not powered to say for certain that patients with other types of HRR mutations do not respond to olaparib, and that metastatic CRPC patients have few treatment options.

It may still be beneficial to use olaparib to treat patients with other HRR mutations beyond BRCA1/2, Efstathiou explained, because even though the survival benefit in cohort B was not statistically significant, the exploratory gene-level analysis performed for PROfound showed a broad range of different mutations and varying responses within that cohort. The range, she said, means the results do not rule out the possibility of benefit for specific genes. Some of these other HRR mutations are rare in the population, and the trial was not powered to determine whether olaparib had a benefit in these gene-specific subgroups.

In his presentation of the data, Mateo noted this caveat as well. "Cohort B was more of an exploratory exercise," he said, pointing out that the trial was not designed for gene-by-gene analysis, but that the results made it clear that performing one was necessary.

Still, the question remains in the wake of the gene-level analysis as to whether patients with non-BRCA1/2 HRR gene mutations should be treated with olaparib. Efstathiou believes they should be, but with close monitoring.

"The positivity of the trial is mainly driven by BRCA2 mutations," Efstathiou said. "That's really obvious. But we cannot isolate that and say, 'It doesn't work [on the others].' You have to look at the patients as a group."

Efstathiou pointed out, for instance, that PROfound's exploratory analyses revealed a wide range of responses among patients with CDK12 mutations, which was unexpected and has since heightened interest in this subgroup in the context of PARP inhibition.

"Beyond the statistical design of the trial, I try to look at it from the side of the patient," she added. "Are you just going to say to a patient, 'Well, if you don't have a BRCA mutation, it's not going to work?' You don't know that, so you have to give them that chance."

In the hypothetical case where she does end up treating a patient with a non-BRCA1/2 HRR gene alteration with olaparib, the onus then is on the physician to closely follow his response on the drug. "That's what we're there for," Efstathiou said.

PROfound implications for the community

The FDA's approval of olaparib in this patient population, along with the recent approval of Clovis Oncology's PARP inhibitor rucaparib (Rubraca) for previously treated, metastatic CRPC patients with BRCA1/2 mutations, represent a shift toward targeted therapy in a cancer type that historically has not benefitted from precision oncology to the degree as other cancers have, Efstathiou said.

Although guidelines have recommended molecular testing for DNA damage repair mutations among patients with high-risk, localized or metastatic prostate cancer and those with a strong family history of cancer since 2018, test results didn't have treatment implications until the olaparib and rucaparib approvals.

Efstathiou sees the need for a "culture shift" in the treatment landscape for metastatic CRPC — one in which all oncologists get into the habit of routinely applying these guidelines and testing patients for molecular alterations. Unfortunately, as of now, she noted that molecular testing in prostate cancer is not the norm. "Out of 20 patients who come to see me for a second opinion, only one usually has had even germline mutation testing," she said.

Efstathiou further emphasized that oncologists need to break the habit of treating patients sequentially upon progression with drugs that share the same mechanism of action. Specifically, she said, PROfound confirms that treating patients with a hormonal agent after they have already progressed on a hormonal agent previously is not an effective strategy. This was the strategy used to treat patients in PROfound's control arm, which has raised eyebrows among oncologists who feel the decision to provide enzalutamide or abiraterone in the study was unethical.

"The problem [with this trial] is the control group," Grönberg said in his discussion at ESMO, and reminded his oncologist colleagues that "we should never forget that we treat real patients [on these trials] and not just study participants." He emphasized further that oncologists should always strive to give patients at least the standard of care with known efficacy.

However, in Efstathiou's experience, oncologists in the real world routinely prescribe enzalutamide or abiraterone to metastatic CRPC patients who have previously received one of these drugs and progressed. She shared an example of a patient with particularly aggressive disease who came to her for a second opinion after being treated with abiraterone followed by enzalutamide followed by apalutamide (Janssen's Erleada) within a period of nine months, and then came to see her at a point when he was "so sick that he could not be exposed to any other drug."

"That is exactly what PROfound looked at," Efstathiou said. "Should we switch from one agent to another that is a similar mechanism of action? No, we shouldn't."