Precision medicine improves survival outcomes for patients with metastatic castration-resistant prostate cancer with BRCA gene alterations

• Approximately 10% of patients with metastatic castration-resistant prostate cancer have alterations in the BRCA1 or BRCA2 genes which are associated with more aggressive disease and a poorer prognosis.

• Published in the Journal of Clinical Oncology, exploratory analysis led by VHIO’s Joaquin Mateo concludes that monotherapy with PARPi olaparib shows a  three-fold increase in radiographic progression-free survival from a median of 3 months in the control arm to 9.8 months in the olaparib-treated patients. Overall survival also increased in the olaparib arm with a median of 19.1 months versus 14.7 months in patients receiving a second hormone therapy.

• Results of this present analysis deepen insights into the data from the phase III PROfound clinical trial—which led to the U.S. Federation of Food and Drug Administration and the European Medicines Agency’s (EMA) approval of olaparib for the treatment of metastatic castration-resistant prostate cancer with DNA damage repair gene mutations—toward advancing precision medicine for the treatment of this patient population.

Led by Joaquin Mateo, Principal Investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Prostate Cancer Translational Research Group and Medical Oncologist at the Vall d’Hebron University Hospital (HUVH), post-hoc analysis of data from the phase III PROfound study shows that monotherapy with the PARP inhibitor olaparib improved radiographic progression-free survival and overall survival compared with a second hormone treatment with enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA gene mutations whose disease had progressed on prior hormone therapy. These observations have now been published in the Journal of Clinical Oncology ⁽¹⁾ .

With an estimated almost 1.4 million new cases and 375,000 deaths worldwide, prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men in 2020 ⁽²⁾. Prostate cancer is the second most diagnosed cancer in Spain, the first among men, with an estimated 29,000 news cases in 2023 ⁽³⁾.

Most cases are diagnosed at early stages of disease and curable with surgery or radiotherapy. However, some of these tumors metastasize and ultimately become resistant to standard-of-care hormone therapy or castration. Furthermore, 10% of cases are diagnosed already at metastatic stages and require systemic therapy upfront.

“While there are several treatment options for patients with metastatic castration-resistant prostate cancer, outcomes remain poor with clinical trials reporting a median overall survival of approximately three years following diagnosis, and life expectancy in real-world practice is closer to two years. Developing new, more precise treatment approaches therefore represents an unmet clinical need,” says Joaquin Mateo, first and corresponding author of this present study.

Approximately 20-25% of patients with mCRPC have different alterations in DNA damage repair pathways, including homologous recombination repair (HRR) genes, particularly in the BRCA2 gene (7-12% of patients). PROfound was a phase III randomized, open-label trial of olaparib versus physicians’ choice of abiraterone or enzalutamide for patients with mCRPC with alterations in genes implicated in DNA damage repair who had experienced disease progression on a prior next-generation hormone agent. Results of PROfound ⁽⁴⁾ led to the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), and others’ regulatory approval of olaparib in this patient population.

“In previous studies with PARP inhibitors we have observed that the response and duration of response differ in patients harboring BRCA gene mutations which is why we decided to further explore the PROFound trial data,” explains Mateo.

387 patients participated in this study, 160 of whom had alterations in BRCA genes (13 in BRCA1 only, 128 in BRCA2 only, and 19 in BRCA1 and/or BRCA2 plus another gene). In the overall population of patients with BRCA mutations, radiographic progression-free survival was 9.8 months with olaparib versus 3 months in the control group. This improvement was only observed in patients harboring alterations in BRCA2, with a median radiographic progression-free survival of 10.8 months in patients treated with olaparib compared with 3.5 months in the control arm. Median overall survival was 20.1 months in patients with BRCA mutations who received olaparib and 14.4% months in patients treated with abiraterone or enzalutamide.

Improved responses were observed in patients with hereditary BRCA mutations as well as in those with alterations that had occurred spontaneously “indicating that the response to olaparib monotherapy was not affected by the time of mutation occurrence, which could therefore be of relevance in treatment planning. Identifying the origin of these alterations is nonetheless important in the management of patients to identify the risk of hereditary cancer in families.”

While these present findings could help to more precisely guide treatment decision making for patients with BRCA mutations, not all individuals with this genetic profile respond to olaparib, and responses can be very different in each individual case. 

“We have observed that some patients respond to treatment for only a few months while in others, responses can last for more than two years. More research is required to identify the underlying causes for these differences and better define which patients could derive the most benefit from this treatment,” concludes Mateo.

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References:

1. Mateo J, de Bono JS, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Agarwal N, Olmos D, Thiery-Vuillemin A, Özgüroğlu M, Mehra N, Matsubara N, Young Joung J, Padua C, Korbenfeld E, Kang J, Marshall H, Lai Z, Barnicle A, Poehlein C, Lukashchuk N, Hussain M. Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial. J Clin Oncol. 2023 Nov 14:JCO2300339. doi: 10.1200/JCO.23.00339. Epub ahead of print. PMID: 37963304.

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. 

1. Las cifras del cáncer en España 2023. 2023. Sociedad Española de Oncología Médica (SEOM).

1. Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Roubaud G, Özgüroğlu M, Kang J, Burgents J, Gresty C, Corcoran C, Adelman CA, de Bono J; PROfound Trial Investigators. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Dec 10;383(24):2345-2357.