Earlier this year, the Pharmaceutical Benefits Scheme (PBS) expanded its indication for LYNPARZA (olaparib) to include patients with metastatic castration-resistant prostate cancer (mCRPC), with pathogenic breast cancer (BRCA1, BRCA2) gene mutations.^1,2 Medical oncologists have been familiar with this poly (ADP-ribose) polymerase inhibitor (PARPi) for ovarian, peritoneal, fallopian cancers, pancreatic and breast cancers.^4,5 To explore the application of LYNPARZA (olaparib) in the mCRPC setting, the limbic met with Dr Francis Parnis, a medical oncologist at Icon Cancer Centre Adelaide.

“Having options is important,” began Dr Parnis. “But this option isn’t like the one we have in the ovarian or breast cancer space. Because although we’ve all likely experienced the use of LYNPARZA in those settings, there are differences in the patient experience with mCRPC as compared to our patients with pre-treated platinum-based chemotherapies. It may surprise some to realise just how well treatment can be tolerated when you don’t have the damage inflicted by prior myelotoxic regimens,” he said.

The Australian Therapeutic Goods Administration (TGA) indication for the use of LYNPARZA in mCRPC is based on the phase III randomised, open-label, multicentre trial PROfound. LYNPARZA 300mg twice daily was compared to a choice of either enzalutamide or abiraterone acetate in patients with mCRPC who had progressed on prior new hormonal agent (NHA) therapy and had a mutation in the homologous recombination repair (HRR) pathway confirmed by prospective central testing. While the trial included patients with gene mutations other than BRCA1/2, in Australia treatment is limited to patients with mutations in only these genes. In the trial, previous taxane chemotherapy was allowed, but not required in all patients.⁶ Dr Parnis explained the clinical significance of the trial: “The risk:benefit ratio favours the BRCA1/2 mutations, which highlights the need to focus efforts on genetic testing to carefully select the appropriate patient for treatment.”

According to the NCCN guidelines, prostate cancer is often associated with somatic mutations occurring in the tumour but not the germline.⁷ It’s estimated that 89% of mCRPC tumours contain a potentially actionable mutation, with only 9% occurring in the germline.⁷  Whilst tumour testing has the potential to identify germline mutations, it doesn’t necessarily distinguish between them.^7-9  There are several reasons why further germline testing can be important, one notably is to inform other potential at-risk family members.⁷  Individuals with germline BRCA mutations are at risk of prostate cancer occurring earlier, being more aggressive, and associated with reduced survival times than non-carrier patients.⁷ If somatic testing identifies or suspects a mutation in a gene(s) linked to cancer predisposition, then referral to a genetic counsellor for further confirmatory germline testing is also advised.⁸

Navigating the PBS for LYNPARZA in mCRPC

“Eligibility is based on a clearly demonstrated BRCA1/2 mutation,” explained Dr Parnis. “In the PBS language, that means a class 4 or 5 gene mutation, with class 4 being a likely pathogenic-allelic variant with probabilities in favour of pathogenicity ranging from 0.95 to 0.99 and class 5 is determined as definitely pathogenic – an allelic variant with a probability of being pathogenic >0.99.”¹⁰  Other criteria include:

(i) must not be subsidised in combination with chemotherapy or an NHA (the condition must have progressed following prior treatment with an NHA)

(ii) the patient must be fit enough for treatment (defined as a WHO performance status of 2 or less).¹

Dr Parnis pointed out that clinicians have a window of opportunity in which to act and seek genetic testing to make the most of the opportunity to treat with this agent. “It can be an involved process,” he explained. “As treating clinicians, we need to think a few steps ahead. One must wait for the disease to become castrate-resistant, yet screen promptly when someone is really ready for treatment. At the moment, I am thinking a few months ahead to be prepared. But as genetic testing lead times shorten, we may find ourselves with some more room to move,” he added.

Challenges facing clinicians in testing patients who have lived for decades with their PC diagnosis

Dr Parnis elaborated on some of the challenges genetic testing poses, specifically around tumour testing: “There are some patients who have had their prostate removed years ago and we know the quality of the results depend on the quality of the sample you are testing. Tumour testing is ideal because you can pick up both germline and somatic mutations. As each occurs at around 5% prevalence, if you aren’t testing the tumour, you’re potentially missing out on screening for 50% of the possible mutations. The other point to be wary of is using the right form and item numbers when ordering tests. Check the forms from your preferred testing centre as there are, in fact, different item numbers for somatic versus germline tests.”

As Dr Parnis explained that the recommendation to test tumour tissue is to identify relevant mutations, testing looks for homologous recombination gene mutations in BRCA1 and BRCA2 genes alongside other genes of interest.⁷   In the literature, it has been reported that somatic mutations may also change over time due to genetic instability and selective pressure from therapy. Thus, repeat testing during the disease course may be appropriate and may possibly address issues of old samples.⁸ The current MBS item for tissue testing is restricted to once a lifetime, so there would be a cost to the patient for the additional test.

In summary, Dr Parnis reiterated how clinicians can be prepared to utilise LYNPARZA as a tool in mCRPC  patients:

1. Test upon mCRPC diagnosis (no prerequisite for prior taxane therapy)
2. Use the tumour sample, where possible, to test
3. ‘In my experience, there is a different patient treatment experience with olaparib in mCRPC, given the lack of platinum-based toxicities in these patients compared to the experience in breast and ovarian cancer patients’

Disclosure

This article was sponsored by Astra Zeneca. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Lynparza product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References

1. Commonwealth of Australia. Department of Health. Olaparib. The Pharmaceutical Benefit Scheme [Cited July 2022]. Available from: https://www.pbs.gov.au
2. Commonwealth of Australia. Department of Health. Expanded PBS listing for metastatic castration-resistant prostate cancer in patients with specific pathogenic gene variants. Minsters, Department of Health. 2022 April 1 [Cited July 2022]. Available from: ttps://www.health.gov.au/
3. George DJ et al. Clin Genitourinary Cancer 2020;18(4):284–94.
4. United States Government. US Food and Drug administration. Lynparza Product Information. Reference ID: 4610866 [cited July. 2022]. Available from :https://www.accessdata.fda.gov
5. Commonwealth of Australia. Department of Health. Making more cancer drugs affordable for all Australians. Minsters, Department of Health. 2017 February 1 [Cited July 2022]. Available from: ttps://www.health.gov.au/
6. De Bono J et al. N Engl J Med. 2020;382(22):2091–02
7. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer: NCCN Evidence Blocks.™ Version 3.2022 – January 10, 2022.
8. Cheng HH et al. J Natl Compr Canc Netw. 2019;17(5):515–21.
9. Parker C et al. Ann Oncol. 2020;31(9):1119–34
10. Radice P et al. Ann Oncol. 2011;22(1):i18-i23.