PME: Prostate cancer is the second most common cancer in male patients and the fifth leading cause of cancer deaths in men globally. How prevalent is the disease in the UK?
NC: Prostate cancer is a major cause of disease and mortality among men and the fifth most common cause of cancer death globally. In the UK, between 40,000 and 50,000 men are diagnosed with prostate cancer every year. Approximately 20% of patients with advanced prostate cancer will develop castration-resistant disease (CRPC) within five years. This occurs when prostate cancer becomes resistant to standard treatment with androgen deprivation therapy (ADT).

Most CRPCs are metastatic (mCRPC), meaning the cancer has spread to a site distant from the prostate. This carries a poor prognosis as overall survival for patients with mCRPC is approximately three years in clinical trial settings. This may be shorter in the patients presenting in everyday practice. Not all patients with mCRPC are fit to receive the most active first-line treatment for mCRPC, and those that go on to receive further treatment thereafter often have diminishing benefit of subsequent therapies.

PME: How have the COVID-19 pandemic and the current socio-economic status affected prostate cancer care?
NC: The latest research published by The National Prostate Cancer Audit in England and Wales (www.npca.org.uk) has shown that COVID-19 decreased the number of men presenting for diagnosis and it changed the way treatment was delivered during periods of lockdown. This may affect the outcome for men with this disease in the future. The study found a small but significant rise in the proportion of men diagnosed with late-stage prostate cancer, as well as an increase in the proportion of men diagnosed following attendance at their local A&E department.

A further report published in September 2022 by the National Prostate Cancer Audit team also showed that there was a significant north/south divide in relation to prostate cancer diagnosis.

This was particularly true for men presenting for the first time with the most aggressive types of this disease, and the report also showed that the poor and socially disadvantaged did significantly worse.

PME: What is the role of PARP inhibitors in targeting DNA damage repair in advanced metastatic prostate cancer?
NC: Recent new developments in prostate cancer treatment have shown that the use of a new class of inhibitor drugs known as PARP inhibitors are active in prostate cancer.

‘COVID-19 decreased the number of men presenting for diagnosis and changed the way treatment was delivered during periods of lockdown’

These were originally shown to be active when used alone in patients who had a specific type of damage to mechanisms that repair DNA. However, recent additional information has shown evidence that the combination of a PARP inhibitor with the newer and more powerful anti-androgenic drugs can be effective, irrespective of the presence of DNA repair mutations.

PME: How does Lynparza work to treat prostate cancer?
NC: Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as those with mutations in BRCA1 and/or BRCA2. Inhibition of PARP with olaparib leads to the trapping of PARP bound to DNA single-strand breaks and the stalling of critical areas in the DNA repair process known as ‘replication forks’, leading to their collapse and the generation of DNA double-strand breaks. A double-strand break results in cancer cell death.

In the PROpel phase 3 trial, olaparib is combined with abiraterone, a novel hormonal agent (NHA) that targets the androgen receptor (AR) pathway. AR signalling engages the nuclear mechanisms in the cell nucleus, stimulating activity that is critical for tumour cell growth and survival in prostate cancer.

In addition, the AR also plays a role in repairing DNA damage in prostate cancer cells, including damage not normally repaired by HRR, the mechanism targeted by PARP inhibition.

Laboratory models have suggested a number of potential mechanisms that could account for increased combination efficacy in both HRR deficient and HRR proficient prostate cancer. Recent data provides evidence that PARP facilitates AR-DNA binding in the presence of DNA damage and that combined inhibition of PARP with olaparib and AR activity with an NHA results in enhanced DNA damage and anti-tumour activity in non-HRRm prostate cancer models.

PME: How significant is the increase in patient survival rates that Lynparza offers when combined with abiraterone?
NC: PROpel is a global, randomised, double-blind, placebo-controlled phase 3 trial assessing the combination of olaparib plus abiraterone versus abiraterone and placebo in first-line metastatic castration-resistant prostate cancer (mCRPC).

In PROpel, combination of olaparib plus abiraterone met the trial’s primary endpoint, demonstrating a significant improvement in radiographic progression-free survival (rPFS) – a 34% reduction in the risk of radiographic disease progression or death – when compared to abiraterone plus placebo. Median radiographic progression-free survival [rPFS] was 24.8 months and 16.6 months, respectively, by investigator assessment.

This data has shown that the combination of olaparib plus abiraterone extends the median rPFS beyond two years, which is the longest published rPFS seen to date in this patient population.

The results showed a favourable trend towards improved overall survival (OS) with olaparib plus abiraterone versus abiraterone plus placebo from the first to the most recent data analysis.

Most recently, updated OS results were presented at the 2023 ASCO Genitourinary Cancers Symposium in February, showing the final pre-specified analysis of the PROpel trial.

This analysis showed a favourable trend towards improved survival in the overall trial population treated with olaparib plus abiraterone versus abiraterone plus placebo: this was consistent with prior pre-planned data analyses.

The median OS for patients treated with olaparib plus abiraterone reached 42.1 months vs 34.7 months for those treated with abiraterone plus placebo. This represents a 7.4-month absolute difference in median OS when compared to standard of care.

While this numerical increase in median OS did not achieve statistical significance, it builds on the meaningful survival gains achieved for patients in this setting treated with abiraterone alone, a current standard of care, and is the longest median OS reported to date in a phase 3 trial in first-line mCRPC.

PME: What are the other tumour types Lynparza is already approved for?
NC: Lynparza is currently approved in prostate, breast, ovarian and pancreatic cancer.

PME: Is the drug as effective for prostate cancer as it is for other cancers?
NC: As a clinician focusing on prostate cancer and other genito-urinary malignancies, my professional focus is on genitourinary so I can only comment on the efficacy of olaparib and abiraterone in prostate cancer.

mCRPC is the most advanced form of prostate cancer and, as I mentioned earlier, the prognosis is generally poor in the long term, and that ‘long term’ is relatively short: most patients do not live beyond three years. To make a difference and ensure that this treatment outcome is optimised, we should aim to deliver the most effective treatments as first-line therapy for this form of the disease.

The results of PROpel have consistently shown that olaparib plus abiraterone has the potential to provide significant therapeutic benefits to patients with mCPRC.

‘In the UK, between 40,000 and 50,000 men are diagnosed with prostate cancer every year’

In addition, the combination is generally well tolerated, with a predictable side-effect profile and no detriment to quality of life compared to other standard treatments, increasing the opportunity for the majority of patients to stay on therapy until progression.

Based on the results of PROpel trial, olaparib plus abiraterone has been approved the EU and several other countries for the treatment of patients with mCRPC. Hopefully, this drug combination can be offered to even more patients worldwide in the future.

PME: With a number of similar drugs currently being developed for combination treatment with novel hormone agents used in prostate cancer, how has drug development for this disease improved in the last ten years?
NC: Historically in the treatment of mCRPC, hormonal therapy has been used to control prostate cancer growth, with chemotherapy also provided as an option. Substantial improvements in outcome have been demonstrated serially using ADT and chemotherapy/NHA combinations when these are used earlier in the disease cycle. However, in the mCRPC stage, options have been more limited.

Over the last decade we have seen advancement in precision medicine using specific drugs, externally directed radiotherapy and targeted systemic radionuclide therapy, all of which have brought significant improvements in cancer patient care.

Further understanding of DNA damage response (DDR) and the role it plays in cancer is enabling us to push these research efforts still further, targeting a broad range of cancers, including those that are aggressive and difficult to treat.

PARP inhibitors are clearly important in targeting the DNA damage-related aspect of this disease, but when the disease becomes castrate resistant (mCRPC), then the disease is clearly at a relatively late stage.

It is therefore critical to research novel treatment solutions earlier in the treatment pathway, as we know that the outcomes from combination systemic treatment are better than when the same combinations are given in late stage disease.

This research is ongoing and I am hopeful that we now have three out of four studies of PARP inhibitors in combination NHAs that demonstrate benefit. This is, of course, for a broader group of mCRPC patients in the first-line setting, but it potentially opens the door for these agents to be used earlier in the disease pathway.

Noel Clarke is Urological Surgeon and Professor of Urological Oncology at Manchester’s Christie/Salford Royal Hospitals and Manchester University